U.S. patent application number 11/415940 was filed with the patent office on 2006-11-23 for quinine formulations.
Invention is credited to Kristin Arnold, Jie Du, Richard Howard Roberts.
Application Number | 20060263427 11/415940 |
Document ID | / |
Family ID | 37022975 |
Filed Date | 2006-11-23 |
United States Patent
Application |
20060263427 |
Kind Code |
A1 |
Roberts; Richard Howard ; et
al. |
November 23, 2006 |
Quinine formulations
Abstract
Disclosed herein are controlled-release quinine formulations and
methods of preparing the same. Also disclosed are methods of
preventing or treating malaria, leg cramps, or babesiosis by
administering the controlled-release quinine formulations. The
controlled-release quinine formulations may help to reduce or
eliminate adverse side effects typically associated with the dosing
of quinine.
Inventors: |
Roberts; Richard Howard;
(Lakewood, NJ) ; Arnold; Kristin; (Morrisville,
PA) ; Du; Jie; (Lansdale, PA) |
Correspondence
Address: |
CANTOR COLBURN, LLP
55 GRIFFIN ROAD SOUTH
BLOOMFIELD
CT
06002
US
|
Family ID: |
37022975 |
Appl. No.: |
11/415940 |
Filed: |
May 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60729574 |
Oct 24, 2005 |
|
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60677269 |
May 3, 2005 |
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Current U.S.
Class: |
424/468 ;
514/305 |
Current CPC
Class: |
A61K 9/4866 20130101;
A61K 9/2027 20130101; A61K 9/2054 20130101; A61K 9/485 20130101;
A61P 33/06 20180101; Y02A 90/10 20180101; A61P 21/02 20180101; A61K
31/44 20130101; A61K 9/2846 20130101; A61P 21/00 20180101; A61K
9/2013 20130101; A61K 9/2018 20130101; A61P 33/02 20180101; A61K
31/49 20130101; Y02A 50/30 20180101; A61K 9/2068 20130101; A61K
31/4745 20130101; G16H 20/10 20180101 |
Class at
Publication: |
424/468 ;
514/305 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 9/22 20060101 A61K009/22; A61K 31/4745 20060101
A61K031/4745 |
Claims
1. (canceled)
2. A controlled-release formulation, comprising: a therapeutically
effective amount of quinine and a release-retarding material;
wherein the release-retarding material is a release-retarding
matrix, a release-retarding coating, or a combination comprising at
least one of the foregoing; and wherein dosing of the
controlled-release formulation results in a reduction in severity
or elimination of an adverse side effect associated with dosing of
an immediate-release quinine formulation.
3. The formulation of claim 2, wherein the adverse side effect is
cinchonism, tinnitus, blurred vision, thrombocytopenia,
granulomatous hepatitis, skin rash, acute interstitial nephritis,
thrombotic thrombocytopenia purpura-hemolytic-uremic syndrome
(TTP-HUS), QT interval prolongation, QTc interval prolongation,
agranulocytosis, hypoprothrombinemia, disseminated intravascular
coagulation, hemolytic anemia, hemolytic uremic syndrome, headache,
diplopia, confusion, altered mental status, seizures, coma,
pruritus, flushing of the skin, sweating, occasional edema of the
face, exanthema, urticaria, erythema multiforme, purpura,
photosensitivity, contact dermatitis, acral necrosis, cutaneous
vasculitis, asthmatic symptoms, tachycardia, irregular rhythm,
premature ventricular contractions (PVCs), nodal escape beats
followed the PVCs, U waves with normal PR, QRS, and QT intervals,
ventricular fibrillation, arrhythmia, nausea and vomiting,
abdominal pain, diarrhea, visual disturbances, including sudden
loss of vision, blindness, diminished visual fields, fixed
papillary dilatation, disturbed color vision, hearing loss,
deafness, or a combination comprising at least one of the
foregoing.
4. The formulation of claim 2, wherein the adverse side effect is
QT interval prolongation or QTc interval prolongation.
5. The controlled-release formulation of claim 2, wherein dosing of
the controlled-release formulation does not cause significant QT
prolongation according to the standards of the United States Food
and Drug Administration.
6. The formulation of claim 2, wherein the quinine is quinine
sulfate; quinine sulfate, dihydrate; quinine hydrochloride; quinine
dihydrochloride; or a combination comprising at least one of the
foregoing.
7. (canceled)
8. The method of claim 36, wherein the release-retarding matrix is
an acrylic or acrylate polymer, an acrylic or acrylate copolymer,
an alkylcellulose, a shellac, a zein, a hydrogenated vegetable oil,
a hydrogenated castor oil, a polyvinylpyrrolidine, a crosslinked
polyvinylpyrrolidone, a vinyl acetate copolymer, a polyethylene
oxide, a wax, a digestible long chain substituted or unsubstituted
hydrocarbon, a fatty alcohol, a fatty acid, a fatty acid ester, a
hydrogenated fat, a polymer or copolymer of lactic or glycolic
acid, a polyalkylene glycol, a hydroxyalkylcellulose, a crosslinked
hydroxyalkylcellulose, a carboxyalkylcellulose, a crosslinked
carboxyalkylcellulose, a hydroxyalkyl alkylcellulose, a
carboxyalkyl starch, a polyvinyl alcohol, a potassium
methacrylate/divinylbenzene copolymer, or a combination comprising
at least one of the foregoing release-retarding materials.
9. (canceled)
10. The method of claim 36, wherein the release-retarding coating
is an alkylcellulose, a hydroxyalkylcellulose, a hydroxyalkyl
alkylcellulose, a carboxyalkylcellulose, a carboxyalkyl
alkylcellulose, a carboxyalkylcellulose ester, a starch, a
polysaccharide, a carrageenan, a galactomannan, traganth,
agar-agar, gum arabicum, guar gum, xanthan gum, an acrylic or
acrylate polymer, polyvinylalcohol, polyvinylpyrrolidone, a
copolymer of polyvinylpyrrolidone and vinyl acetate, a polyalkylene
oxide, or a combination comprising at least one of the foregoing
release-retarding coatings; and wherein the coating optionally
further comprises a plasticizer.
11. (canceled)
12. The method of claim 36, wherein the controlled-release coating
coats a granule, a particle, a tablet, a bead, or a combination
comprising at least one of the foregoing.
13. (canceled)
14. The method of claim 36, wherein the controlled-release
formulation is an oral dosage formulation, wherein the oral dosage
formulation is a tablet, a capsule, a liquid, a suspension, an
emulsion, an orally disintegrating tablet, a fast-dissolve tablet
dosage formulation, a chewable tablet, a gastro-resistant tablet, a
gastro-resistant capsule, an osmotic pump, or a combination
comprising at least one of the foregoing.
15.-22. (canceled)
23. The controlled-release formulation of claim 2, wherein the
controlled-release formulation provides therapeutically effective
plasma levels for greater than about 16 hours after administration
at steady state.
24. The method of claim 36, wherein the controlled-release
formulation provides therapeutically effective plasma levels for
greater than about 16 hours after administration at steady
state.
25. The method of claim 36, wherein T.sub.max of the
controlled-release quinine formulation is about 1.5 to about 8
hours.
26. The method of claim 36, wherein the C.sub.max is about 200 to
about 7000 ng/mL and the C.sub.min is about 100 to about 3500 ng/mL
at 12 to 24 hours, when at steady state.
27. The method of claim 36, wherein the duration of 50% or greater
of C.sub.max is about 10 to about 20 hours; or wherein the duration
of 80% or greater of C.sub.max is about 2 to about 12 hours.
28.-29. (canceled)
30. The method of claim 36, wherein the formulation is prepared
into a unit dosage form that exhibits a dissolution profile such
that at 60 minutes after combining the dosage form with 900 ml of a
dissolution medium at 37.degree. C..+-.0.5.degree. C. according to
USP 28<711> test method 2 (paddle), 75 rpm paddle speed,
about 10 to about 30 weight percent of the total amount of quinine
is released, and wherein after 10 hours greater than or equal to
about 70% of the total amount of quinine is released.
31. (canceled)
32. The method of claim 36, wherein the formulation is prepared
into a unit dosage form that exhibits a dissolution profile such
that at 60 minutes after combining the dosage form with 900 ml of
purified water at 37.degree. C..+-.0.5.degree. C. according to USP
28<711> test method 2 (paddle), 75 rpm paddle speed, about 10
to about 30 weight percent of the total amount of quinine is
released, and wherein after 10 hours greater than or equal to about
70% of the total amount of quinine is released.
33. (canceled)
34. The method of claim 36, wherein the formulation is prepared
into a unit dosage form that exhibits a dissolution profile such
that at 2 hours after combining the dosage form with 900 ml of a
0.1 N Hydrochloric Acid medium at 37.degree. C..+-.0.5.degree. C.
according to USP 28 <711> test method 1 or 2, about 0 to
about 50 weight percent of the total amount of quinine is released
and wherein after 2 hours when the medium is switched to a buffer
phase of pH 4.5, 6.8, 7.0 or water, about 0 to about 100 weight
percent of the total amount of quinine is released.
35. (canceled)
36. A method of treating a patient, comprising administering a
controlled-release quinine formulation to a patient, wherein the
controlled-release formulation comprises a therapeutically
effective amount of quinine and a release-retarding material;
wherein the release-retarding material is a release-retarding
matrix, a release-retarding coating, or a combination comprising at
least one of the foregoing; and wherein the controlled-release
formulation provides therapeutically effective plasma levels for
greater than about 12 hours after administration at steady
state.
37. (canceled)
38. A controlled-release formulation, comprising: a therapeutically
effective amount of quinine and a release-retarding material;
wherein the release-retarding material is a release-retarding
matrix, a release-retarding coating, or a combination comprising at
least one of the foregoing; and wherein the release-retarding
matrix is an alkylcellulose, a shellac, a zein, a hydrogenated
vegetable oil, a hydrogenated castor oil, a polyvinylpyrrolidine, a
crosslinked polyvinylpyrrolidone, a vinyl acetate copolymer, a wax,
a digestible long chain substituted or unsubstituted hydrocarbon, a
fatty alcohol, a fatty acid, a fatty acid ester, a hydrogenated
fat, a crosslinked hydroxyalkylcellulose, a polyvinyl alcohol, or a
combination comprising at least one of the foregoing
release-retarding materials; and wherein the release-retarding
coating is alkylcellulose, a hydroxyalkylcellulose, a hydroxyalkyl
alkylcellulose, a starch, a polysaccharide, agar-agar, gum
arabicum, guar gum, xanthan gum, polyvinylalcohol,
polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone and vinyl
acetate, a polyalkylene oxide, or a combination comprising at least
one of the foregoing release-retarding coatings; and wherein the
coating optionally further comprises a plasticizer.
39. The formulation of claim 38, wherein the matrix further
comprises a polyethylene oxide, a polyalkylene glycol, an acrylic
or acrylate polymer, an acrylic or acrylate copolymer, a polymer or
co-polymer of lactic or glycolic acid, a crosslinked
carboxyalkylcellulose, a carboxyalkyl starch, a potassium
methacrylate/divinylbenzene copolymer, a carboxyalkylcellulose, a
hydroxyalkyl alkylcellulose, a hydroxyalkylcellulose, or a
combination comprising at least one of the forgoing; wherein the
release-retarding coating further comprises an acrylic or acrylate
polymer, a carboxyalkylcellulose, a carboxyalkyl alkylcellulose, a
carboxyalkylcellulose ester, a carrageenan, a galactomannan,
traganth, or a combination comprising at least one of the
forgoing
40. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/729,574, filed Oct. 24, 2005 and U.S.
Provisional Application Ser. No. 60/677,269, filed May 3, 2005,
both of which are incorporated by reference in their entirety.
BACKGROUND
[0002] Malaria is a parasitic disease caused by the Plasmodium
species P. falciparum, P. vivax, P. ovale and P. malariae. The
malaria parasite causes intermittent fevers and chills. It affects
multiple organs and systems, including red blood cells, the
kidneys, liver, spleen and brain. It is estimated by the World
Health Organization (WHO) that up to 500 million persons per year
are infected with malaria, with 200 to 300 million people suffering
from malaria at any given time (See Roll Back Malaria. World Health
Organization. available at:
www.rbm.who.int/cmc_upload/0/000/015372/RBMInfosheet.sub.--1.htm).
Up to 3 million will die each year. If P. falciparum infection goes
untreated or is not treated appropriately, general observations
indicate that mortality is high, killing up to 25% of non-immune
adults within 2 weeks of a primary attack [Taylor T E, Strickland G
T. Malaria. In: Strickland G T, ed. Hunter's Tropical Medicine and
Emerging Infectious Diseases. 8th ed. Philadelphia, Pa.: W.B.
Saunders Company; 2000.] A significant number of these cases are
found in Central America, South America, Asia, and Africa. Known
antimalarial agents include 9-aminoacridines (e.g. mepacrine),
4-aminoquinolines (e.g. amodiaquine, chloroquine,
hydroxychloroquine), 8-aminoquinolines (e.g. primaquine,
quinocide), biguanides with an inhibiting effect on dihydrofolic
acid reductase (e.g. chlorproguanil, cycloguanil, proguanil),
diaminopyrimidines (e.g. pyrimethamine), quinine salts, sulphones
such as dapsone, sulphonamides, sulphanilamides and antibiotics
such as tetracycline.
[0003] Quinine (cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-) is an
antiprotozoal and an antimyotonic, and is known for the treatment
of malaria caused by Plasmodium species, the treatment and
prophylaxis of nocturnal recumbency leg muscle cramps, and the
treatment of babesiosis caused by Babesia microti. Quinine is
structurally similar to quinidine, which is also an antiprotozoal,
but can function as an antiarrhythmic. Quinidine has been
associated with the prolongation of the QT interval in a
dose-related fashion. Prolongation of the electrocardiographic QT
interval can be indicative of delayed ventricular repolarization.
Excessive QT prolongation has been associated with an increased
risk of ventricular arrhythmia. Although quinine is a diastereomer
of quinidine, it does not cause QT prolongation to the same degree
although it has been suggested that patients with a history of
cardiac arrhythmias or QT prolongation should carefully consider
taking quinine as they may be at risk for arrhythmias.
[0004] There remains a need in the art for quinine formulations
that provide a desired therapeutic effect against certain diseases
(e.g., malaria) while at the same time minimizing the adverse side
effects associated with dosing of quinine.
SUMMARY
[0005] Disclosed herein are controlled-release quinine and quinine
combination formulations, as well as methods of using such
controlled-release formulations for therapeutic purposes. Exemplary
therapeutic purposes include the treatment or prevention malaria;
leg cramps including nocturnal recumbency leg muscle cramps,
idiopathic leg cramps, and leg cramps caused by athletic exertion;
and babesiosis caused by Babesia microti.
[0006] In one embodiment, a controlled-release formulation
comprises a therapeutically effective amount of quinine; wherein
dosing of the controlled-release formulation results in reducing or
eliminating an adverse side effect associated with dosing of an
immediate-release quinine formulation.
[0007] In another embodiment, a method of reducing the severity or
eliminating an adverse side effect associated with the
administration of an immediate-release quinine formulation
comprises administering to a patient a controlled-release quinine
formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 Mean plasma concentrations and QTc measurements over
24-hours following a single oral dose of Quinine Sulfate under
fasting conditions;
[0009] FIG. 2 Mean plasma concentrations and QTc measurements over
24-hours following a single oral dose of Quinine Sulfate under fed
conditions;
[0010] FIG. 3 FIG. 3 Mean plasma concentration and QTc measurements
over 24-hours following a single oral dose of Quinine Sulfate 324
mg under fasting conditions;
[0011] FIG. 4 Mean plasma concentration and QTc measurements over
24-hours following a single oral dose of Quinine Sulfate 648 mg
under fasting conditions.
DETAILED DESCRIPTION
[0012] Quinine therapy can be considered optimal when effective
plasma levels are reached when required. In addition, peak plasma
values (C.sub.max) should be as low as possible so as to reduce the
incidence and severity of possible side effects, including the
adverse event of QT prolongation. For the convenience of the
patient or caretaker, a quinine dosage form that can be
administered once daily and yields effective plasma levels for 8 to
24 hours would be desirable.
[0013] Controlled-release forms of quinine or its pharmaceutically
acceptable salt may be found to provide a reduction in adverse side
effects often associated with dosing immediate-release forms of
quinine of the same dosage strength. Described herein are
controlled-release quinine formulations, methods of preparing, and
methods of use thereof.
[0014] The controlled-release quinine formulations may provide a
decrease in adverse side effects that are associated with high
doses of quinine, or even those associated with therapeutic doses.
Such adverse side effects that can be mitigated include, for
example, cinchonism, tinnitus, blurred vision, thrombocytopenia,
granulomatous hepatitis, skin rash, acute interstitial nephritis,
thrombotic thrombocytopenia purpura-hemolytic-uremic syndrome
(TTP-HUS), QT interval prolongation, QTc interval prolongation,
agranulocytosis, hypoprothrombinemia, disseminated intravascular
coagulation, hemolytic anemia, hemolytic uremic syndrome, headache,
diplopia, confusion, altered mental status, seizures, coma,
pruritus, flushing of the skin, sweating, occasional edema of the
face, exanthema, urticaria, erythema multiforme, purpura,
photosensitivity, contact dermatitis, acral necrosis, cutaneous
vasculitis, asthmatic symptoms, tachycardia, irregular rhythm,
premature ventricular contractions (PVCs), nodal escape beats
followed the PVCs, U waves with normal PR, QRS, and QT intervals,
ventricular fibrillation, arrhythmia, nausea and vomiting,
abdominal pain, diarrhea, visual disturbances, including sudden
loss of vision, blindness, diminished visual fields, fixed
papillary dilatation, disturbed color vision, hearing loss, and
deafness.
[0015] As used herein, the controlled-release quinine formulation,
as compared to immediate-release formulations (e.g. dosed TID), may
provide reduction in the duration or magnitude of QT prolongation
events as determined by surface electrocardiogram (EKG) measured
from the beginning of the QRS complex to the end of the T wave,
which represents the duration of activation and recovery of the
ventricular myocardium. The QT values are heart rate corrected to
"QTc". Generally, a QTc above about 0.44 seconds is considered
abnormal, although there are age- and sex-specific abnormal QTc
values which vary from this number.
[0016] As used herein, the term "wherein dosing of the
controlled-release formulation does not cause significant QT
prolongation according to the standards of the United States Food
and Drug Administration" means the standards found in the document
Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic
Drugs, U.S. Department of Health and Human Services Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
Center for Biologics Evaluation and Research (CBER) issued October
2005 and available at
http://www.fda.gov/cder/guidance/index.htm.
[0017] The controlled-release formulations of quinine or its
pharmaceutically acceptable salts are formulated to provide more
consistent plasma levels of quinine and the active metabolite
3-hydroxyquinine than immediate-release forms. More consistent
plasma levels may result in the reduction of the duration of QT or
QTc interval prolongation that may otherwise be associated with
increased doses or "dose dumping" of quinine. Furthermore, more
consistent plasma levels may also result in the reduction or
avoidance of other adverse side effects as outline previously.
[0018] An additional advantage to a controlled-release formulation,
especially extended-release, is an increase in patient compliance
and ease of dispensing for the pharmacist as there will be fewer
dosage forms to count and package. Currently, immediate-release
oral dosage tablets of quinine sulfate used to treat P. falciparum
or babesiosis are commonly dosed at 600-650 mg every eight hours.
By reducing the number of doses per day as well as potentially
reducing or eliminating certain adverse side effects, patients
would comply more strictly to prescribed dosing regimens. Increased
compliance to the dosing regimen provides an increased chance of a
successful treatment to the particular disease or disorder
targeted.
[0019] Generally, suitable extended-release forms include wax or
polymer coated tablets, caplets, or drug cores; time-release
matrices; or a combination comprising at least one of the
foregoing. Other dosage forms for oral administration include, for
example, suspension, an emulsion, orally disintegrating tablets
including effervescent tablets, chewable tablets, gastro-resistant
tablets, soft capsules, hard capsules, gastro-resistant capsules,
coated granules, gastro-resistant granules, modified-release
granules, osmotic pumps, and the like. Examples of extended-release
formulations which are suitable for use with quinine or salts
thereof include those provided in Sustained Release Medications,
Chemical Technology Review No. 177. Ed. J. C. Johnson. Noyes Data
Corporation 1980; and Controlled Drug Delivery, Fundamentals and
Applications, 2nd Edition. Eds. J. R. Robinson, V. H. L. Lee.
Mercel Dekker Inc. New York 1987. Additional forms are described in
U.S. Pat. Nos. 5,102,666 and 5,422,123.
[0020] An "active agent" means a compound, element, or mixture that
when administered to a patient, alone or in combination with
another compound, element, or mixture, confers, directly or
indirectly, a physiological effect on the patient. The indirect
physiological effect may occur via a metabolite or other indirect
mechanism. When the active agent is a compound, then salts,
solvates (including hydrates) of the free compound or salt,
crystalline forms, non-crystalline forms, and any polymorphs of the
compound are contemplated herein.
[0021] "Pharmaceutically acceptable salts" include derivatives of
quinine, wherein the parent compound is modified by making
non-toxic acid addition salts thereof, and further refers to
pharmaceutically acceptable solvates, including hydrates, of such
compounds and such salts. Also included are all crystalline,
amorphous, and polymorph forms. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid addition salts; and the like, and a combination
comprising at least one of the foregoing salts. The
pharmaceutically acceptable salts include non-toxic salts, for
example, from non-toxic inorganic or organic acids. For example,
non-toxic acid salts include those derived from inorganic acids
such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,
nitric and the like. Pharmaceutically acceptable organic salts
includes salts prepared from organic acids such as acetic,
trifluoroacetic, propionic, succinic, glycolic, stearic, lactic,
malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic,
besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic,
HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and the like. Specific
quinine salts include quinine sulfate, quinine hydrochloride,
quinine dihydrochloride, and hydrates thereof.
[0022] "Quinine" as used herein is inclusive of all
pharmaceutically acceptable salt forms, crystalline forms,
amorphous form, polymorphic forms, solvates, and hydrates unless
specifically indicated otherwise. As used herein, quinine sulfate
means cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate (2:1) or
cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate (2:1)
dehydrate unless otherwise indicated.
[0023] "Bioavailability" means the extent or rate at which an
active agent is absorbed into a living system or is made available
at the site of physiological activity. For active agents that are
intended to be absorbed into the bloodstream, bioavailability data
for a given formulation may provide an estimate of the relative
fraction of the administered dose that is absorbed into the
systemic circulation. "Bioavailability" can be characterized by one
or more pharmacokinetic parameters.
[0024] A "dosage form" means a unit of administration of an active
agent. Examples of dosage forms include tablets, capsules,
injections, suspensions, liquids, emulsions, creams, ointments,
suppositories, inhalable forms, transdermal forms, and the like.
The quinine formulation may be a dosage form administered via oral,
buccal, injectable, or transdermal administration.
[0025] By "oral dosage form" is meant to include a dosage form
prescribed or intended for oral administration. An oral dosage form
may or may not comprise a plurality of subunits such as, for
example, microcapsules or microtablets, packaged for administration
in a single dose. The oral dosage form can be in solid or liquid
form.
[0026] By an "effective" amount or a "therapeutically effective
amount" of an active agent is meant a sufficient amount of the
active agent to produce a therapeutic effect in the patient. The
amount that is "effective" will vary from subject to subject,
depending on the age and general condition of the individual, the
particular active agent, and the like. Thus, it is not always
possible to specify an exact "effective amount." However, an
appropriate "effective" amount in any individual case may be
determined by one of ordinary skill in the art using routine
experimentation.
[0027] "Efficacy" means the ability of an active agent administered
to a patient to produce a therapeutic effect in the patient.
[0028] A "patient" means a human or non-human animal in need of
medical treatment. Medical treatment can include treatment of an
existing condition, such as a disease or disorder, prophylactic or
preventative treatment, or diagnostic treatment. In some
embodiments the patient is a human patient. A "caretaker" includes
a worker in the health care field, physicians, pharmacists,
physician's assistants, nurses, aides, caretakers (which can
include family members or guardians), emergency medical workers,
and the like.
[0029] The terms "treating" and "treatment" mean the reduction in
severity or frequency of symptoms, elimination of symptoms or
underlying cause, prevention of the occurrence of symptoms or their
underlying cause, and improvement or remediation of damage.
[0030] A "product" or "pharmaceutical product" means a dosage form
of an active agent and optionally packaging.
[0031] "Safety" means the incidence or severity of adverse events
associated with administration of an active agent, including
adverse effects associated with patient-related factors (e.g., age,
gender, ethnicity, race, target illness, abnormalities of renal or
hepatic function, co-morbid illnesses, genetic characteristics such
as metabolic status, or environment) and active agent-related
factors (e.g., dose, plasma level, duration of exposure, or
concomitant medication).
[0032] By "releasable form" is meant to include immediate-release,
controlled-release, and extended-release forms. Certain release
forms can be characterized by their dissolution profile.
Dissolution profile as used herein, means a plot of the amount of
active ingredient released as a function of time. The dissolution
profile may be measured utilizing the Drug Release Test
<724>, which incorporates standard test USP 28 (Test
<711>) or by other test methods or conditions. A profile is
characterized by the test conditions selected. Thus the dissolution
profile can be generated at a preselected apparatus type, shaft
speed, temperature, volume, and pH of the dissolution media.
[0033] A first dissolution profile can be measured at a pH level
approximating that of the stomach. A second dissolution profile can
be measured at a pH level approximating that of one point in the
intestine or several pH levels approximating multiple points in the
intestine.
[0034] A highly acidic pH may simulate the stomach and a less
acidic to basic pH may simulate the intestine. By the term "highly
acidic pH": it is meant a pH of about 1 to about 4. By the term
"less acidic to basic pH" is meant a pH of greater than about 4 to
about 7.5, specifically about 6 to about 7.5. A pH of about 1.2 can
be used to simulate the pH of the stomach. A pH of about 6 to about
7.5, specifically about 6.8, can be used to simulate the pH of the
intestine.
[0035] "Pharmacokinetic parameters" describe the in vivo
characteristics of an active agent (or surrogate marker for the
active agent) over time, such as plasma concentration (C),
C.sub.max, C.sub.n, C.sub.24, T.sub.max, and AUC. "C.sub.max" is
the measured concentration of the active agent in the plasma at the
point of maximum concentration. "C.sub.n" is the measured
concentration of an active agent in the plasma at about n hours
after administration. "C.sub.24" is the measured concentration of
an active agent in the plasma at about 24 hours after
administration. The term "T.sub.max" refers to the time at which
the measured concentration of an active agent in the plasma is the
highest after administration of the active agent. "AUC" is the area
under the curve of a graph of the measured concentration of an
active agent (typically plasma concentration) vs. time, measured
from one time point to another time point. For example AUC.sub.0-t
is the area under the curve of plasma concentration versus time
from time 0 to time t. The AUC.sub.0-.infin. (AUC.sub..infin.) or
AUC.sub.0-INF (AUC.sub.inf) is the calculated area under the curve
of plasma concentration versus time from time 0 to time
infinity.
[0036] By "immediate-release", it is meant a conventional or
non-modified release in which greater than or equal to about 75% of
the active agent is released within two hours of administration,
specifically within one hour of administration. Alternatively, an
"immediate-release" formulation contains substantially no added
release retarding agents.
[0037] By "controlled-release" it is meant a dosage form in which
the release of the active agent is controlled or modified over a
period of time. Controlled can mean, for example, extended- or
delayed-release at a particular time. Alternatively, controlled can
mean that the release of the active agent is extended for longer
than it would be in an immediate-release dosage form, i.e., at
least over several hours.
[0038] "Sustained-release" or "extended-release" include the
release of the active agent at such a rate that blood (e.g.,
plasma) levels are maintained within a therapeutic range for at
least about 8 hours, specifically at least about 12 hours, and more
specifically at least about 24 hours after administration at
steady-state. The term steady-state means that a plasma level for a
given active agent has been achieved and which is maintained with
subsequent doses of the drug at a level which is at or above the
minimum effective therapeutic level for a given active agent.
[0039] By "delayed-release", it is meant that there is a time-delay
before significant plasma levels of the active agent are achieved.
A delayed-release formulation of the active agent can avoid an
initial burst of the active agent, or can be formulated so that
release of the active agent in the stomach is avoided and
absorption occurrs in the small intestine.
[0040] An extended-release form is a form suitable for providing
controlled-release of quinine over a sustained period of time
(e.g., 8 hours, 12 hours, 24 hours). Extended-release dosage forms
of quinine may release the active agent at a rate independent of
pH, for example, about pH 1.2 to about 7.5. Alternatively,
extended-release dosage forms may release quinine at a rate
dependent upon pH, for example, a lower rate of release at pH 1.2
and a higher rate of release at pH 7.5. Specifically, the
extended-release form avoids dose dumping upon oral administration.
The extended-release oral dosage form can be formulated to provide
for an increased duration of quinine action allowing once-daily or
twice-daily dosing.
[0041] There are several approaches to preparing an
extended-release quinine dosage formulation. Exemplary forms
include polymeric matrices containing quinine, coated tablets,
coated particles, osmotic pump, depot forms, and the like. Each
will be discussed herein below.
[0042] Generally, an extended-release dosage form comprises a
release-retarding material. The release-retarding material can be,
for example, in the form of a matrix or a coating. The quinine in
extended-release form may be, for example, a particle of quinine
that is combined with a release-retarding material. The
release-retarding material is a material that permits release of
the active agent at a sustained rate in an aqueous medium. The
release-retarding material can be selectively chosen so as to
achieve, in combination with the other stated properties, a desired
in vitro release rate.
[0043] Release-retarding materials include, for example acrylic
polymers, alkylcelluloses, shellac, zein, hydrogenated vegetable
oil, hydrogenated castor oil, polyvinylpyrrolidine, vinyl acetate
copolymers, polyethylene oxide, and a combination comprising at
least one of the foregoing materials. The extended-release oral
dosage form can contain between about 1 wt % and about 80 wt % of
the release-retarding material based on the total weight of the
oral dosage form.
[0044] Suitable acrylic polymers that can be used as
release-retarding materials include, for example, acrylic acid and
methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid anhydride), methyl methacrylate,
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, glycidyl
methacrylate copolymers, and a combination comprising at least one
of the foregoing polymers. The acrylic polymer may comprise
methacrylate copolymers described in NF XXIV as fully polymerized
copolymers of acrylic and methacrylic acid esters with a low
content of quaternary ammonium groups.
[0045] Suitable alkylcelluloses include, for example, methyl
cellulose, ethylcellulose, and the like. Those skilled in the art
will appreciate that other cellulosic polymers, including other
alkyl cellulosic polymers, can be substituted for part or all of
the ethylcellulose.
[0046] Other suitable release-retarding materials include neutral
or synthetic waxes, fatty alcohols (such as lauryl, myristyl,
stearyl, cetyl or specifically cetostearyl alcohol), fatty acids,
including fatty acid esters, fatty acid glycerides (mono-, di-, and
tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes,
stearic acid, stearyl alcohol, hydrophobic and hydrophilic
materials having hydrocarbon backbones, and a combination
comprising at least one of the foregoing materials. Suitable waxes
include beeswax, glycowax, castor wax, carnauba wax and wax-like
substances, e.g., material normally solid at room temperature and
having a melting point of from about 30.degree. C. to about
100.degree. C., and a combination comprising at least one of the
foregoing waxes.
[0047] In other embodiments, the release-retarding material may
comprise digestible, long chain (e.g., C.sub.8-C.sub.50,
specifically C.sub.12-C.sub.40), substituted or unsubstituted
hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters
of fatty acids, mineral and vegetable oils, waxes, and a
combination comprising at least one of the foregoing materials.
Hydrocarbons having a melting point of between about 25.degree. C.
and about 90.degree. C. may be used. Specifically, long chain
hydrocarbon materials, fatty (aliphatic) alcohols can be used. The
oral dosage form can contain up to about 60 wt % of a digestible,
long chain hydrocarbon, based on the total weight of the oral
dosage form.
[0048] Further, the extended-release matrix can contain up to about
60 wt % of a polyalkylene glycol.
[0049] Alternatively, the release-retarding material may comprise
polylactic acid, polyglycolic acid, or a co-polymer of lactic and
glycolic acid.
[0050] Alternatively, the release-retarding material can include,
for example, crosslinked sodium carboxymethylcellulose, crosslinked
hydroxypropylcellulose, high molecular weight
hydroxypropylmethylcellulose, carboxymethyl starch, potassium
methacrylate/divinylbenzene copolymer, polymethylmethacrylate,
crosslinked polyvinylpyrrolidone, high molecular weight
polyvinylalcohols, methylcellulose, carboxymethylcellulose, low
molecular weight hydroxypropylmethylcellulose, low molecular weight
polyvinylalcohols, polyethylene glycols, non-crosslinked
polyvinylpyrrolidone, medium viscosity
hydroxypropylmethylcellulose, medium viscosity polyvinylalcohols,
combinations thereof and the like.
[0051] Release-modifying agents, which affect the release
properties of the release-retarding material, can optionally be
used. The release-modifying agent can, for example, function as a
pore-former. The pore former can be organic or inorganic, and
include materials that can be dissolved, extracted or leached from
the material in the environment of use. The pore-former can
comprise one or more hydrophilic polymers, such as
hydroxypropylmethylcellulose, hydroxypropylcellulose,
polycarbonates comprised of linear polyesters of carbonic acid in
which carbonate groups reoccur in the polymer chain, and a
combination comprising at least one of the foregoing
release-modifying agents. Alternatively, the pore-former may be a
small molecule such as lactose, or metal stearates, and a
combination comprising at least one of the foregoing
release-modifying agents.
[0052] The release-retarding material can also optionally include
other additives such as an erosion-promoting agent (e.g., starch
and gums); and/or a semi-permeable polymer. In addition to the
above ingredients, an extended-release dosage form may also contain
suitable quantities of other materials, e.g., diluents, lubricants,
binders, granulating aids, colorants, flavorants and glidants that
are conventional in the pharmaceutical art. The release-retarding
material can also include an exit means comprising a passageway,
orifice, or the like. The passageway can have any shape, such as
round, triangular, square, elliptical, irregular, etc.
[0053] The extended-release dosage form comprising quinine or a
salt thereof and a release-retarding material may be prepared by a
suitable technique for preparing active agents as described in
detail below. The quinine or a salt thereof and release-retarding
material may, for example, be prepared by wet granulation
techniques, melt extrusion techniques, etc. To obtain an
extended-release dosage form, it may be advantageous to incorporate
an additional hydrophobic material.
[0054] The quinine or salt thereof in extended-release form can
include a plurality of substrates (particles such as
microparticles) comprising the active agent, which substrates are
coated with an extended-release coating comprising a
release-retarding material. The extended-release preparations may
thus be made in conjunction with a multiparticulate system, such as
beads, ion-exchange resin beads, spheroids, microspheres, seeds,
pellets, granules, and other multiparticulate systems in order to
obtain a desired extended-release of the quinine or salt thereof.
The multiparticulate system can be presented in a capsule or other
suitable unit dosage form.
[0055] In certain cases, more than one multiparticulate system can
be used, each exhibiting different characteristics, such as pH
dependence of release, time for release in various media (e.g.,
acid, base, simulated intestinal fluid), release in vivo, size, and
composition.
[0056] In some cases, a spheronizing agent, together with the
quinine or salt thereof can be spheronized to form spheroids.
Microcrystalline cellulose and hydrous lactose impalpable are
examples of such agents. Additionally (or alternatively), the
spheroids can contain a water insoluble polymer, specifically an
acrylic polymer, an acrylic copolymer, such as a methacrylic
acid-ethyl acrylate copolymer, or ethyl cellulose. In this
formulation, the extended-release coating will generally include a
water insoluble material such as a wax, either alone or in
admixture with a fatty alcohol, or shellac or zein.
[0057] Spheroids or beads, coated with quinine or a salt thereof
can be prepared, for example, by dissolving or dispersing the
active agent in a solvent and then spraying the solution onto a
substrate, for example, sugar spheres NF, 18/20 mesh, using a
Wurster insert. Optionally, additional ingredients are also added
prior to coating the beads in order to assist the quinine or salt
thereof binding to the substrates, and/or to color the resulting
beads, etc. The resulting substrate-active agent may optionally be
overcoated with a barrier material, to separate the therapeutically
active agent from the next coat of material, e.g.,
release-retarding material. For example, the barrier material is a
material comprising hydroxypropylmethylcellulose. However,
film-formers known in the art may be used.
[0058] To obtain a extended-release of quinine or salt thereof in a
manner sufficient to provide a therapeutic effect for the sustained
durations, the substrate comprising the active agent can be coated
with an amount of release-retarding material sufficient to obtain a
weight gain level from about 2 wt % to about 30 wt %, specifically
about 5 wt % to about 25 wt %, and more specifically about 7 wt %
to about 20 wt %, although the coat can be greater or lesser
depending upon the physical properties of the active agent utilized
and the desired release rate, among other things. Moreover, there
can be more than one release-retarding material used in the coat,
as well as various other pharmaceutical excipients.
[0059] The release-retarding material may thus be in the form of a
film coating comprising a dispersion of a hydrophobic polymer.
Solvents used for application of the release-retarding coating
include pharmaceutically acceptable solvents, such as water,
methanol, ethanol, methylene chloride, and a combination comprising
at least one of the foregoing solvents.
[0060] In addition, the extended-release profile of quinine or salt
thereof (either in vivo or in vitro) can be altered, for example,
by using more than one release-retarding material, varying the
thickness of the release-retarding material, changing the
particular release-retarding material used, altering the relative
amounts of release-retarding material, altering the manner in which
the plasticizer is added (e.g., when the extended-release coating
is derived from an aqueous dispersion of hydrophobic polymer), by
varying the amount of plasticizer relative to retardant material,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, etc.
[0061] The extended-release formulations preferably slowly release
quinine or salt thereof, e.g., when ingested and exposed to gastric
fluids, and then to intestinal fluids. The extended-release profile
of the formulations can be altered, for example, by varying the
amount of retardant, e.g., hydrophobic material, by varying the
amount of plasticizer relative to hydrophobic material, by the
inclusion of additional ingredients or excipients, by altering the
method of manufacture, etc.
[0062] Exemplary forms containing a release-retarding material
coating can comprise quinine blended with a water soluble polymer
that is a film forming polymer. Useful water soluble film forming
polymers are polymers that have an apparent viscosity of 1 to 100
mPas when dissolved in a 2% aqueous solution at 20.degree. C.
solution. For example, the water soluble film forming polymers can
be selected from the group comprising alkylcelluloses such as
methylcellulose, hydroxyalkylcelluloses such as
hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkyl
alkylcelluloses such as hydroxyethyl methylcellulose and
hydroxypropyl methylcellulose, carboxyalkylcelluloses such as
carboxymethylcellulose, alkali metal salts of
carboxyalkylcelluloses such as sodium carboxymethylcellulose,
carboxyalkyl alkylcelluloses such as carboxymethyl ethylcellulose,
carboxyalkylcellulose esters, starches, pectines such as sodium
carboxymethylamylopectine, chitine derivates such as chitosan,
polysaccharides such as alginic acid, alkali metal and ammonium
salts thereof, carrageenans, galactomannans, traganth, agar-agar,
gum arabicum, guar gum and xanthan gum, polyacrylic acids and the
salts thereof, polymethacrylic acids and the salts thereof,
methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone,
copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene
oxides such as polyethylene oxide and polypropylene oxide and
copolymers of ethylene oxide and propylene oxide. Other
pharmaceutically acceptable polymers that exhibit similar as
defined above physico-chemical properties as defined above are
equally suitable.
[0063] Specific water soluble film forming polymers are for example
hydroxypropyl methylcellulose, polymethacrylate,
hydroxypropylcellulose, or a polyvidone; more specifically
hydroxypropyl methylcelluloses (HPMCs). HPMCs contain sufficient
hydroxypropyl and methoxy groups to render it water-soluble. HPMC
having a methoxy degree of substitution from about 0.8 to about 2.5
and a hydroxypropyl molar substitution from about 0.05 to about 3.0
are generally water-soluble. Methoxy degree of substitution refers
to the average number of methyl ether groups present per
anhydroglucose unit of the cellulose molecule. Hydroxypropyl molar
substitution refers to the average number of moles of propylene
oxide which have reacted with each anhydroglucose unit of the
cellulose molecule. Suitable HPMC include those having a viscosity
from about 1 to about 100 mPas, specifically about 3 to about 15
mPas, and more specifically about 5 mPas.
[0064] The weight-by-weight ratio of drug:water soluble film
forming polymer is in the range of about 17:1 to about 1:5,
specifically about 10:1 to about 1:3, and more specifically about
7:1 to about 1:2.
[0065] The particles generally comprise (a) a central, rounded or
spherical core, (b) a layer or a coating film of a water soluble
film forming polymer and quinine or a salt therof, (c) optionally a
barrier polymer layer and (d) a release retarding material coating.
The core can have a diameter of about 250 to about 2000
micrometers, specifically about 600 to about 1500 micrometers, and
yet more specifically about 750 to about 1000 micrometers.
[0066] Materials suitable for use as the cores of the particles
include pharmaceutically acceptable materials that have appropriate
dimensions and firmness. Examples of such materials are polymers
e.g. plastic resins; inorganic substances, e.g. silica, glass,
hydroxyapatite, salts (sodium or potassium chloride, calcium or
magnesium carbonate) and the like; organic substances, e.g.
activated carbon, acids (citric, fumaric, tartaric, ascorbic and
the like acids), and saccharides and derivatives thereof.
Particularly suitable materials are saccharides such as sugars,
oligosaccharides, polysaccharides and their derivatives, for
example, glucose, rhamnose, galactose, lactose, sucrose, mannitol,
sorbitol, dextrin, maltodextrin, cellulose, microcrystalline
cellulose, sodium carboxymethyl cellulose, starches (maize, rice,
potato, wheat, tapioca) and the like saccharides.
[0067] The combination of the water soluble film forming polymer
and quinine can be coated on the core as a layer to form a coated
core.
[0068] In another embodiment, the cores themselves can contain
quinine. The cores containing quinine can be granules or spheroids
(spherical granules) prepared according to art-known methods of
granulation and spheronization.
[0069] The particles can be filled in hard-gelatin capsules such
that a therapeutically effective amount of the active ingredient is
available per dosage form. An desired pharmacokinetic profile (fast
onset, level peak and trough values) can be obtained when about 60
to about 90 weight % of the quinine based on the total amount of
quinine in the dosage form, specifically about 70 to about 80
weight % of the quinine is comprised within the controlled-release
particles and about 10 to about 40 weight %, specifically about 20
to about 30 weight % of the quinine based on the total amount of
quinine in the dosage form, is in an immediate-release form.
[0070] In order to achieve the desired pharmacokinetic profile, the
dosage forms may be filled with particles that release quinine at
different rates, a kind that releases quinine slowly, and a kind
that releases quinine more rapidly, in particular one kind that
releases the active ingredient immediately, e.g. particles as
described that lack the release retarding material coating.
[0071] The different particles may be filled consecutively in the
capsules, or they may be premixed and the thus obtained premix may
be filled into the capsules (taking into account possible
segregation).
[0072] Alternatively, the controlled-release particles may further
comprise a top-coat of a water-soluble polymer as described
hereinbefore and quinine which is released practically immediately
upon ingestion and thus ensures a rapid onset of action.
[0073] In another embodiment, a capsule is filled with
controlled-release particles as described above (about 60 to about
90 weight %, specifically about 70 to about 80 weight % based on
the total weight of quinine in the dosage form) together with one
or more minitablets which comprise the remaining amount of
quinine.
[0074] The quinine formulations can be coated with a material to
delay release of the quinine until the formulation is exposed to
the intestinal tract. These formulations include enteric coated
formulations, which are forms coated with a composition that is
non-toxic and includes a pharmaceutically acceptable enteric
polymer which is predominantly soluble in the intestinal fluid, but
substantially insoluble in the gastric juices. An enteric coating
is a coating that prevents release of the active agent until the
dosage form reaches the small intestine. Enteric coated dosage
forms comprise quinine or a salt thereof coated with an enteric
polymer. Examples include polyvinyl acetate phthalate (PVAP),
hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose
acetate phthalate (CAP), methacrylic acid copolymer, hydroxy propyl
methylcellulose succinate, cellulose acetate succinate, cellulose
acetate hexahydrophthalate, hydroxypropyl methylcellulose
hexahydrophthalate, hydroxypropyl methylcellulose phthalate
(HPMCP), cellulose propionate phthalate, cellulose acetate maleate,
cellulose acetate trimellitate, cellulose acetate butyrate,
cellulose acetate propionate, methacrylic acid/methacrylate polymer
(acid number 300 to 330 and also known as EUDRAGIT L), which is an
anionic copolymer based on methacrylate and available as a powder
(also known as methacrylic acid copolymer, type A NF, methacrylic
acid-methyl methacrylate copolymer, ethyl
methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl
methacrylate copolymer, and the like, and a combination comprising
at least one of the foregoing enteric polymers. Other examples
include natural resins, such as shellac, SANDARAC, copal
collophorium, and a combination comprising at least one of the
foregoing polymers. Yet other examples of enteric polymers include
synthetic resin bearing carboxyl groups. The methacrylic acid:
acrylic acid ethyl ester 1:1 copolymer solid substance of the
acrylic dispersion sold under the trade designation "EUDRAGIT
L-100-55" may be suitable.
[0075] The extended-release quinine formulations can be prepared to
include an immediate-release portion. An exemplary form may provide
at least a part of the dose with an extended-release of quinine and
another part of the formulation with rapid or immediate-release.
The immediate- and extended-release of quinine can be achieved
according to different principles, such as by single dose layered
pellets or tablets, by multiple dose layered pellets or tablets, or
by two or more different fractions of single or multiple dose
layered pellets or tablets, optionally in combination with pellets
or tablets having instant release. Multiple dose layered pellets
may be filled into a capsule or together with tablet excipients
compressed into a multiple unit tablet. Alternatively, a multiple
dose layered tablet may be prepared.
[0076] Pellets or tablets may comprise a core material, optionally
layered on a seed/sphere, the core material comprising quinine
together with a water swellable substance; an optional intermediate
layer surrounding the core; and an outer coating layer containing
quinine in an immediate-release form. Alternatively, the layered
pellets or tablets may comprise a core material comprising quinine;
a surrounding layer comprising a water swellable substance; an
outer coating layer containing quinine in an immediate-release
form; and optional intermediate layers for ease of processing or
improved dosage form stability.
[0077] In another embodiment, part of the quinine is present in an
immediate-release form, for example, as particles lacking a
release-retarding material coating, or as immediate-release
minitablets, or as a topcoat on the extended-release
formulation.
[0078] The quinine or pharmaceutically acceptable salt thereof can
also be formulated with OROS technology (Alza Corporation, Mountain
View, Calif.) also know as an "osmotic pump". Such dosage forms
have a fluid-permeable (semipermeable) membrane wall, an
osmotically active expandable driving member (the osmotic push
layer), and a density element for delivering the active agent. In
an osmotic pump dosage form, quinine may be dispensed through an
exit means comprising a passageway, orifice, or the like, by the
action of the osmotically active driving member. The active agent
of the osmotic pump dosage form may be formulated as a
thermo-responsive formulation in which the quinine is dispersed in
a thermo-responsive composition. Alternatively, the osmotic pump
dosage form may contain a thermo-responsive element comprising a
thermo-responsive composition at the interface of the osmotic push
layer and the quinine composition.
[0079] The term "thermo-responsive" as used herein includes
thermoplastic compositions capable of softening, or becoming
dispensable in response to heat and hardening again when cooled.
The term also includes thermotropic compositions capable of
undergoing changes in response to the application of energy in a
gradient manner. These compositions are temperature sensitive in
their response to the application or withdrawal of energy.
Thermo-responsive compositions typically possess the physiochemical
property of exhibiting solid, or solid-like properties at
temperatures up to about 32.degree. C., and become fluid,
semisolid, or viscous when at temperatures above about 32.degree.
C., usually in about 32.degree. C. to about 40.degree. C.
Thermo-responsive compositions, including thermo-responsive
carriers, have the property of melting, dissolving, undergoing
dissolution, softening, or liquefying and thereby forming a
dispensable composition at the elevated temperatures. The
thermo-responsive carrier can be lipophilic, hydrophilic, or
hydrophobic. Another property of a thermo-responsive carrier is its
ability to maintain the stability of the agent contained therein
during storage and during delivery of the agent. A
thermo-responsive composition can be easily excreted, metabolized,
or assimilated, upon being dispensed into a biological
environment.
[0080] The osmotic pump dosage form comprises a semipermeable
membrane. The capsule or other dispenser of the osmotic pump dosage
form can be provided with an outer wall comprising the selectively
semipermeable material. A selectively permeable material is one
that does not adversely affect a host or animal, is permeable to
the passage of an external aqueous fluid, such as water or
biological fluids, while remaining essentially impermeable to the
passage of the active agent, and maintains its integrity in the
presence of a thermotropic thermo-responsive composition, that is
it does not melt or erode in its presence. The selectively
semipermeable material forming the outer wall is substantially
insoluble in body fluids, nontoxic, and non-erodible.
[0081] Representative materials for forming the selectively
semipermeable wall include semipermeable homopolymers,
semipermeable copolymers, and the like. Suitable materials include,
for example, cellulose esters, cellulose monoesters, cellulose
diesters, cellulose triesters, cellulose ethers, cellulose
ester-ethers, and a combination comprising at least one of the
foregoing materials. These cellulosic polymers have a degree of
substitution, D.S., on their anhydroglucose unit from greater than
0 up to 3 inclusive. By degree of substitution is meant the average
number of hydroxyl groups originally present on the anhydroglucose
unit that are replaced by a substituting group, or converted into
another group. The anhydroglucose unit can be partially or
completely substituted with groups such as acyl, alkanoyl, aroyl,
alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkylcarbamate,
alkylcarbonate, alkylsulfonate, alkylsulfamate, and like
semipermeable polymer forming groups.
[0082] Other selectively semipermeable materials include, for
example, cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose diacetate, cellulose
triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-
and tri-alkenylates, mono-, di- and tri-aroylates, and the like,
and a combination comprising at least one of the foregoing
materials. Exemplary polymers including cellulose acetate having a
D.S. of 1.8 to 2.3 and an acetyl content of about 32 to about
39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl
content of about 21 to about 35%; cellulose triacetate having a D.S
of 2 to 3 and an acetyl content of about 34 to about 44.8%, and the
like. More specific cellulosic polymers include cellulose
propionate having a D.S. of 1.8 and a propionyl content of about
38.5%; cellulose acetate propionate having an acetyl content of
about 1.5 to about 7% and an propionyl content of about 39 to about
42%; cellulose acetate propionate having an acetyl content of about
2.5 to about 3%, an average propionyl content of about 39.2 to
about 45% and a hydroxyl content of about 2.8 to about 5.4%;
cellulose acetate butyrate having a D.S. of 1.8, an acetyl content
of about 13 to about 15%, and a butyryl content of about 34 to
about 39%; cellulose acetate butyrate having an acetyl content of
about 2 to about 29.5%, a butyryl content of about 17 to about 53%,
and a hydroxyl content of about 0.5 to about 4.7%; cellulose
triacylates having a D.S. of 2.9 to 3 such as cellulose
trivalerate, cellulose trilaurate, cellulose tripalmitate,
cellulose trioctanoate, and cellulose tripropionate; cellulose
diesters having a D.S. of 2.2 to 2.6 such as cellulose disuccinate,
cellulose dipalmitate, cellulose dioctanoate, cellulose dicarpylate
and the like; mixed cellulose esters such as cellulose acetate
valerate, cellulose acetate succinate, cellulose propionate
succinate, cellulose acetate octanoate, cellulose valerate
palmitate, cellulose acetate heptanoate, and the like, and a
combination comprising at least one of the foregoing polymers.
[0083] Additional selectively semipermeable polymers include, for
example, acetaldehyde dimethyl cellulose acetate, cellulose acetate
ethylcarbamate, cellulose acetate methylcarbamate, cellulose
dimethylaminoacetate, semi-permeable polyamides, semipermeable
polyurethanes, semi-permeable polysulfanes, semipermeable
sulfonated polystyrenes, cross-linked, selectively semipermeable
polymers formed by the coprecipitation of a polyanion and a
polycation, selectively semipermeable silicon rubbers,
semipermeable polystyrene derivates, semipermeable poly(sodium
styrenesulfonate), semipermeable poly(vinylbenzyltrimethyl)
ammonium chloride polymers, and a combination comprising at least
one of the foregoing polymers.
[0084] The osmotically expandable driving member, or osmotic push
layer, of the osmotic pump dosage form is swellable and expandable
inner layer. The materials used for forming the osmotic push layer,
are neat polymeric materials, and/or polymeric materials blended
with osmotic agents that interact with water or a biological fluid,
absorb the fluid, and swell or expand to an equilibrium state. The
polymer should exhibit the ability to retain a significant fraction
of imbibed fluid in the polymer molecular structure. Such polymers
may be, for example, gel polymers that can swell or expand to a
very high degree, usually exhibiting about a 2 to 50-fold volume
increase. Swellable, hydrophilic polymers, also known as
osmopolymers, can be non-cross-linked or lightly cross-linked. The
cross-links can be covalent or ionic bonds with the polymer
possessing the ability to swell but not dissolve in the presence of
fluid. The polymer can be of plant, animal or synthetic origin.
Polymeric materials useful for the present purpose include
poly(hydroxyalkyl methacrylate) having a molecular weight of about
5,000 to about 5,000,000, poly(vinylpyrrolidone) having a molecular
weight of about 10,000 to about 360,000, anionic and cationic
hydrogels, poly(electrolyte) complexes, poly(vinyl alcohol) having
a low acetate residual, a swellable mixture of agar and
carboxymethyl cellulose, a swellable composition comprising methyl
cellulose mixed with a sparingly crosslinked agar, a
water-swellable copolymer produced by a dispersion of finely
divided copolymer of maleic anhydride with styrene, ethylene,
propylene, or isobutylene, water swellable polymer of N-vinyl
lactams, and the like, and a combination comprising at least one of
the foregoing polymers. Other gellable, fluid imbibing and
retaining polymers useful for forming the osmotic push layer
include pectin having a molecular weight ranging of about 30,000 to
about 300,000, polysaccharides such as agar, acacia, karaya,
tragacanth, algins and guar, acidic carboxy polymer and its salt
derivatives, polyacrylamides, water-swellable indene maleic
anhydride polymers; polyacrylic acid having a molecular weight of
about 80,000 to about 200,000; POLYOX, polyethylene oxide polymers
having a molecular weight of about 100,000 to about 5,000,000, and
greater, starch graft copolymers, polyanions and polycations
exchange polymers, starch-polyacrylonitrile copolymers, acrylate
polymers with water absorbability of about 400 times its original
weight, diesters of polyglucan, a mixture of cross-linked polyvinyl
alcohol and poly(N-vinyl-2-pyrrolidone), zein available as
prolamine, poly(ethylene glycol) having a molecular weight of about
4,000 to about 100,000, and the like, and a combination comprising
at least one of the foregoing polymers.
[0085] The osmotically expandable driving layer of the osmotic pump
dosage form may further contain an osmotically effective compound
(osmagent) that can be used neat or blended homogeneously or
heterogeneously with the swellable polymer, to form the osmotically
expandable driving layer. Such osmagents include osmotically
effective solutes that are soluble in fluid imbibed into the
swellable polymer, and exhibit an osmotic pressure gradient across
the semipermeable wall against an exterior fluid. Suitable
osmagents include, for example, solid compounds such as magnesium
sulfate, magnesium chloride, sodium chloride, lithium chloride,
potassium sulfate, sodium sulfate, mannitol, urea, sorbitol,
inositol, sucrose, glucose, and the like, and a combination
comprising at least one of the foregoing osmagents. The osmotic
pressure in atmospheres, atm, of the osmagents may be greater than
about zero atm, and generally about zero atm to about 500 atm, or
higher.
[0086] The swellable, expandable polymer of the osmotically
expandable driving layer, in addition to providing a driving source
for delivering the active agent from the dosage form, may also
function as a supporting matrix for an osmotically effective
compound. The osmotic compound can be homogeneously or
heterogeneously blended with the polymer to yield the desired
expandable wall or expandable pocket. The composition in a
presently preferred embodiment comprises (a) a polymer and an
osmotic compound, or (b) a solid osmotic compound. Generally, a
composition will comprise about 20 wt % to about 90 wt % of polymer
and about 10 wt % to about 80 wt % of osmotic compound, with a
presently preferred composition comprising about 35 wt % to about
75 wt % of polymer and about 25 wt % to about 65 wt % of osmotic
compound, based on the total weight of the composition.
[0087] The quinine of the osmotic pump dosage form may be
formulated as a thermo-responsive formulation in which the quinine
is dispersed in a thermo-responsive composition. Alternatively, the
osmotic pump dosage form may contain a thermo-responsive element
comprising a thermo-responsive composition at the interface of the
osmotic push layer and the quinine composition. Representative
thermo-responsive compositions and their melting points are as
follows: Cocoa butter (32.degree. C.-34.degree. C.), cocoa butter
plus 2% beeswax (35.degree. C.-37.degree. C.), propylene glycol
monostearate and distearate (32.degree. C.-35.degree. C.),
hydrogenated oils such as hydrogenated vegetable oil (36.degree.
C.-37.5.degree. C.), 80% hydrogenated vegetable oil and 20%
sorbitan monopalmitate (39.degree. C.-39.5.degree. C.), 80%
hydrogenated vegetable oil and 20% polysorbate 60, (36.degree.
C.-37.degree. C.), 77.5% hydrogenated vegetable oil, 20% sorbitan
trioleate, 2.5% beeswax and 5.0% distilled water, (37.degree.
C.-38.degree. C.), mono-, di-, and triglycerides of acids having
from 8-22 carbon atoms including saturated and unsaturated acids
such as palmitic, stearic, oleic, lineolic, linolenic and
archidonic; triglycerides of saturated fatty acids with mono- and
diglycerides (34.degree. C.-35.5.degree. C.), propylene glycol
mono- and distearates 3(33.degree. C.-34.degree. C.), partially
hydrogenated cottonseed oil (35.degree. C.-39.degree. C.), a block
polymer of polyoxy-alkylene and propylene glycol; block polymers
comprising 1,2-butylene oxide to which is added ethylene oxide;
block copolymers of propylene oxide and ethylene oxide, hardened
fatty alcohols and fats (33.degree. C.-36.degree. C.), hexadienol
and hydrous lanolin triethanolamine glyceryl monostearate
(38.degree. C.), eutectic mixtures of mono-, di-, and triglycerides
(35.degree. C.-39.degree. C.), WITEPSOL#15, triglyceride of
saturated vegetable fatty acid with monoglycerides (33.5.degree.
C.-35.5.degree. C.), WITEPSOL H32 free of hydroxyl groups
(31.degree. C.-33.degree. C.), WITEPSOL W25 having a saponification
value of 225-240 and a melting point of (33.5.degree.
C.-35.5.degree. C.), WITEPSOL E75 having a saponification value of
220-230 and a melting point of (37.degree. C.-39.degree. C.), a
polyalkylene glycol such as polyethylene glycol 1000, a linear
polymer of ethylene oxide (38.degree. C.-41.degree. C.),
polyethylene glycol 1500 (38.degree. C.-41.degree. C.),
polyethylene glycol monostearate (39.degree. C.-42.5.degree. C.),
33% polyethylene glycol 1500, 47% polyethylene glycol 6000 and 20%
distilled water (39.degree. C.-41.degree. C.), 30% polyethylene
glycol 1500, 40% polyethylene glycol 4000 and 30% polyethylene
glycol 400, (33.degree. C.-38.degree. C.), mixture of mono-, di-,
and triglycerides of saturated fatty acids having 11 to 17 carbon
atoms, (33.degree. C.-35.degree. C.), and the like. The
thermo-responsive compositions, including thermo-responsive
carriers are useful for storing the active agent in a solid
composition at a temperature of about 20.degree. C. to about
33.degree. C., maintaining an immiscible boundary at the swelling
composition interface, and for dispensing the agent in a flowable
composition at a temperature greater than about 33.degree. C. and
specifically between about about 33.degree. C. and about 40.degree.
C.
[0088] The amount of quinine present in the osmotic pump dosage
form is about 10 mg to about 2 g or more. The osmotic dosage form
may be formulated for once daily or less frequent
administration.
[0089] The quinine of the osmotic pump dosage form may be
formulated by a number of techniques known in the art for
formulating solid and liquid oral dosage forms. The quinine of the
osmotic pump dosage form may be formulated by wet granulation. In
an exemplary wet granulation method, the quinine and the
ingredients comprising the quinine layer are blended using an
organic solvent, such as isopropyl alcohol-ethylene dichloride
80:20 v:v (volume:volume) as the granulation fluid. Other
granulating fluid such as denatured alcohol 100% may be used for
this purpose. The ingredients forming the quinine layer are
individually passed through a screen such as a 40-mesh screen and
then thoroughly blended in a mixer. Next, other ingredients
comprising the active agent layer are dissolved in a portion of the
granulation fluid, such as the cosolvent described above. Then the
latter prepared wet blend is slowly added to the active agent blend
with continual mixing in the blender. The granulating fluid is
added until a wet blend is produced, which wet mass then is forced
through a screen such as a 20-mesh screen onto oven trays. The
blend is dried for about 18 to about 24 hours at about 30.degree.
C. to about 50.degree. C. The dry granules are sized then with a
screen such as a 20-mesh screen. Next, a lubricant is passed
through a screen such as an 80-mesh screen and added to the dry
screen granule blend. The granulation is put into milling jars and
mixed on a jar mill for about 1 to about 15 minutes. The push layer
may also be made by the same wet granulation techniques. The
compositions are pressed into their individual layers in a KILIAN
press-layer press.
[0090] Another manufacturing process that can be used for providing
the quinine layer and osmotically expandable driving layer
comprises blending the powered ingredients for each layer
independently in a fluid bed granulator. After the powered
ingredients are dry blended in the granulator, a granulating fluid,
for example, poly(vinyl-pyrrolidone) in water, or in denatured
alcohol, or in 95:5 ethyl alcohol/water, or in blends of ethanol
and water is sprayed onto the powders. Optionally, the ingredients
can be dissolved or suspended in the granulating fluid. The coated
powders are then dried in a granulator. This process granulates the
ingredients present therein while adding the granulating fluid.
After the granules are dried, a lubricant such as stearic acid or
magnesium stearate is added to the granulator. The granules for
each separate layer are pressed then in the manner described
above.
[0091] The quinine formulation and osmotic push layer of the
osmotic dosage form may also be manufactured by mixing quinine with
composition forming ingredients and pressing the composition into a
solid lamina possessing dimensions that correspond to the internal
dimensions of the compartment. In another manufacture, quinine and
other quinine composition-forming ingredients and a solvent are
mixed into a solid, or a semisolid, by methods such as ballmilling,
calendaring, stirring or rollmilling, and then pressed into a
preselected layer forming shape. Next, a layer of a composition
comprising an osmopolymer and an optional osmagent are placed in
contact with the layer comprising the quinine. The layering of the
first layer comprising the quinine and the second layer comprising
the osmopolymer and optional osmagent composition can be
accomplished by using a conventional layer press technique. The
semipermeable wall can be applied by molding, spraying or dipping
the pressed bilayer's shapes into wall forming materials. An air
suspension coating procedure which includes suspending and tumbling
the two layers in current of air until the wall forming composition
surrounds the layers is also used to form the semi-permeable wall
of the osmotic dosage forms.
[0092] The dispenser of the osmotic pump dosage form may be in the
form of a capsule. The capsule may comprise an osmotic hard capsule
and/or an osmotic soft capsule. The osmotic hard capsule may be
composed of two parts, a cap and a body, which are fitted together
after the larger body is filled with the active agent. The osmotic
hard capsule may be fitted together by slipping or telescoping the
cap section over the body section, thus completely surrounding and
encapsulating the active agent. Hard capsules may be made by
techniques known in the art.
[0093] The soft capsule of the osmotic pump dosage form may be a
one-piece osmotic soft capsule. Generally, the osmotic soft capsule
is of sealed construction encapsulating the active agent. The soft
capsule may be made by various processes, such as the plate
process, the rotary die process, the reciprocating die process, and
the continuous process.
[0094] Materials useful for forming the capsule of the osmotic pump
dosage form are commercially available materials including gelatin,
gelatin having a viscosity of about 5 to about 30 millipoises and a
bloom strength up to about 150 grams; gelatin having a bloom value
of about 160 to about 250; a composition comprising gelatin,
glycerine, water and titanium dioxide; a composition comprising
gelatin, erythrosin, iron oxide and titanium dioxide; a composition
comprising gelatin, glycerine, sorbitol, potassium sorbate and
titanium dioxide; a composition comprising gelatin, acacia,
glycerin, and water; and the like, and a combination comprising at
least one of the foregoing materials.
[0095] The semipermeable wall forming composition can be applied to
the exterior surface of the capsule in laminar arrangement by
molding, forming, air spraying, dipping or brushing with a
semipermeable wall forming composition. Other techniques that can
be used for applying the semipermeable wall are the air suspension
procedure and the pan coating procedures. The air suspension
procedure includes suspending and tumbling the capsule arrangement
in a current of air and a semipermeable wall forming composition
until the wall surrounds and coats the capsule. The procedure can
be repeated with a different semipermeable wall forming composition
to form a semipermeable laminated wall.
[0096] Exemplary solvents suitable for manufacturing the
semipermeable wall include inert inorganic and organic solvents
that do not adversely harm the materials, the capsule wall, the
active agent, the thermo-responsive composition, the expandable
member, or the final dispenser. Solvents for manufacturing the
semipermeable wall may be aqueous solvents, alcohols, ketones,
esters, ethers, aliphatic hydrocarbons, halogenated solvents,
cycloaliphatics, aromatics, heterocyclic solvents, and a
combination comprising at least one of the foregoing solvents.
Particular solvents include acetone, diacetone alcohol, methanol,
ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl
ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol
monoethyl ether, ethylene glycol monoethyl acetate, methylene
dichloride, ethylene dichloride, propylene dichloride, carbon
tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl
ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene,
naphtha, 1,4-dioxane, tetrahydrofuran, water, and mixtures thereof
such as acetone and water, acetone and methanol, acetone and ethyl
alcohol, methylene dichloride and methanol, and ethylene
dichloride, methanol, and a combination comprising at least one of
the foregoing solvents. The semipermeable wall may be applied at a
temperature a few degrees less than the melting point of the
thermo-responsive composition. Alternatively, the thermo-responsive
composition can be loaded into the dispenser after applying the
semipermeable wall.
[0097] The exit means or hole in the osmotic pump dosage form, for
releasing the active agent, can be formed by mechanical or laser
drilling, or by eroding an erodible element in the wall, such as a
gelatin plug. The orifice can be a polymer inserted into the
semipermeable wall, which polymer is a porous polymer and has a
pore, or which polymer is a microporous polymer and has a
micro-pore.
[0098] Other extended-release formulations can include those that
are easily administered for those patients that have difficulty
with oral solid dosage formulations, such as tablets and capsules.
Such formulations would be useful for the very young and elderly
patients who require dosage forms that are easy to swallow. Easily
administered formulations, such as chewable tablets, gummy forms,
candy forms, sprinkle forms, liquid formulations (e.g. suspensions
or emulsions), taste-masked formulations, and fast dissolve
tablets, are thus desirable.
[0099] For easy administration, the extended-release form can be a
chewable tablet containing quinine or a salt thereof. A chewable
tablet comprises a chewable base and optionally a sweetener. The
chewable base comprises an excipient such as, for example,
mannitol, sorbitol, lactose, or a combination comprising at least
one of the foregoing excipients. The optional sweetener used in the
chewable dosage form may be, for example, digestible sugars,
sucrose, liquid glucose, sorbitol, dextrose, isomalt, liquid
maltitol, aspartame, lactose, and a combination comprising at least
one of the foregoing sweeteners. In certain cases, the chewable
base and the sweetener may be the same component. The chewable base
and optional sweetener may comprise about 50 wt % to about 90 wt %
of the total weight of the dosage form.
[0100] The chewable dosage form may additionally contain
preservatives, agents that prevent adhesion to oral cavity and
crystallization of sugars, flavoring agents, souring agents,
coloring agents, and a combination comprising at least one of the
foregoing agents. Glycerin, lecithin, hydrogenated palm oil or
glyceryl monostearate may be used as a protecting agent of
crystallization of the sugars in an amount of about 0.04 wt % to
about 10 wt % of the total weight of the ingredients, to prevent
adhesion to oral cavity and improve the soft property of the
products. Additionally, isomalt or liquid maltitol may be used to
enhance the chewing properties of the chewable dosage form.
[0101] Since quinine is bitter tasting, it can be taste-masked for
better patient compliance. Quinine may be present in
microparticles, wherein each microparticle incorporates quinine or
a salt thereof in conjunction with a protective material. The
microparticle may be provided as a microcapsule or as a matrix-type
microparticle. Microcapsules may incorporate a discrete mass of
quinine or a salt thereof surrounded by a discrete, separately
observable coating of the protective material. Conversely, in a
matrix-type particle, the quinine or a salt thereof is dissolved,
suspended or otherwise dispersed throughout the protective
material. Certain microparticles may include attributes of both
microcapsules and matrix-type particle. For example, a
microparticle may incorporate a core incorporating a dispersion of
quinine or a salt thereof in a first protective material and a
coating of a second protective material, which may be the same as
or different from the first protective material surrounding the
core. Alternatively, a microparticle may incorporate a core
consisting essentially of quinine or a salt thereof and a coating
incorporating the protective material, the coating itself having
some of the quinine or a salt thereof dispersed within it.
Specifically protective material can be a release-retarding
material and/or taste-masking material.
[0102] The microparticles can have a mean outside diameter of up to
about 600 micrometers, specifically about 75 to about and 500
micrometers, and more specifically about 150 to about 500
micrometers. Microparticles above about 200 micrometers may be
used. Thus, the microparticles may be between about 200 mesh and
about 30 mesh U.S. standard size, and more specifically between
about 100 mesh and about 35 mesh.
[0103] Sprinkle dosage forms include particulate or pelletized
forms of quinine or a salt thereof, optionally having functional or
non-functional coatings, with which a patient or a caregiver can
sprinkle the particulate/pelletized dose into drink or onto soft
food. A sprinkle dosage form may comprise particles of about 10 to
about 100 micrometers in their major dimension. Sprinkle dosage
forms may be in the form of optionally coated granules or as
microcapsules. Specifically the sprinkle dosage forms are
extended-release formulations. See U.S. Pat. No. 5,084,278, which
is hereby incorporated by reference for its teachings regarding
microcapsule formulations, which may be administered as sprinkle
dosage forms.
[0104] Another oral dosage form is a non-chewable, fast dissolving
dosage form of quinine. These dosage forms can be made by methods
known to those of ordinary skill in the art of pharmaceutical
formulations. For example, Cima Labs has produced oral dosage forms
including microparticles and effervescents, which rapidly
disintegrate in the mouth and provide adequate taste-masking. Cima
Labs has also produced a rapidly dissolving dosage form containing
the active agent and a matrix that includes a nondirect compression
filler and a lubricant. U.S. Pat. No. 5,178,878 and U.S. Pat. No.
6,221,392 provide teachings regarding fast-dissolve dosage
forms.
[0105] An exemplary fast dissolve dosage form includes a mixture
incorporating a water and/or saliva activated effervescent
disintegration agent and microparticles. The microparticles can
include those previously described for the chewable forms. The
mixture including the microparticles and effervescent
disintegration agent desirably may be present as a tablet of a size
and shape adapted for direct oral administration to a patient. The
tablet is substantially completely disintegrable upon exposure to
water and/or saliva. The effervescent disintegration agent is
present in an amount effective to aid in disintegration of the
tablet, and to provide a distinct sensation of effervescence when
the tablet is placed in the mouth of a patient.
[0106] The effervescent sensation is not only pleasant to the
patient but also tends to stimulate saliva production, thereby
providing additional water to aid in further effervescent action.
Thus, once the tablet is placed in the patient's mouth, it will
disintegrate rapidly and substantially completely without any
voluntary action by the patient. Even if the patient does not chew
the tablet, disintegration will proceed rapidly. Upon
disintegration of the tablet, the microparticles are released and
can be swallowed as a slurry or suspension of the microparticles.
The microparticles thus may be transferred to the patient's stomach
for dissolution in the digestive tract and systemic distribution of
the pharmaceutical ingredient.
[0107] The term effervescent disintegration agent(s) includes
compounds which evolve gas. The preferred effervescent agents
evolve gas by means of chemical reactions which take place upon
exposure of the effervescent disintegration agent to water and/or
to saliva in the mouth. The bubble or gas generating reaction is
most often the result of the reaction of a soluble acid source and
an alkali metal carbonate or carbonate source. The reaction of
these two general classes of compounds produces carbon dioxide gas
upon contact with water included in saliva.
[0108] Such water activated materials may be kept in a generally
anhydrous state with little or no absorbed moisture or in a stable
hydrated form since exposure to water will prematurely disintegrate
the tablet. The acid sources or acid may be those which are safe
for human consumption and may generally include food acids, acid
anhydrides and acid salts. Food acids include citric acid, tartaric
acid, malic acid, fumaric acid, adipic acid, and succinic acids
etc. Because these acids are directly ingested, their overall
solubility in water is less important than it would be if the
effervescent tablet formulations were intended to be dissolved in a
glass of water. Acid anhydrides and acid of the above described
acids may also be used. Acid salts may include sodium, dihydrogen
phosphate, disodium dihydrogen pyrophosphate, acid citrate salts
and sodium acid sulfite.
[0109] Carbonate sources include dry solid carbonate and
bicarbonate salts such as sodium bicarbonate, sodium carbonate,
potassium bicarbonate and potassium carbonate, magnesium carbonate
and sodium sesquicarbonate, sodium glycine carbonate, L-lysine
carbonate, arginine carbonate, amorphous calcium carbonate, and a
combination comprising at least one of the foregoing
carbonates.
[0110] The effervescent disintegration agent is not always based
upon a reaction which forms carbon dioxide. Reactants which evolve
oxygen or other gasses which are safe are also considered within
the scope. Where the effervescent agent includes two mutually
reactive components, such as an acid source and a carbonate source,
it is preferred that both components react substantially
completely. Therefore, an equivalent ratio of components which
provides for equal equivalents is preferred. For example, if the
acid used is diprotic, then either twice the amount of a
mono-reactive carbonate base, or an equal amount of a di-reactive
base should be used for complete neutralization to be realized.
However, the amount of either acid or carbonate source may exceed
the amount of the other component. This may be useful to enhance
taste and/or performance of a tablet containing an overage of
either component. In this case, it is acceptable that the
additional amount of either component may remain unreacted.
[0111] In general, the amount of effervescent disintegration agent
useful for the formation of tablets is about 5 wt % to about 50 wt
% of the final composition, specifically about 15 wt % and about 30
wt % thereof, and most specifically about 20 wt % to about 25 wt %
of the total composition.
[0112] Other fast dissolving quinine dosage forms can be prepared
without an effervescent agent using spray dried carbohydrate or
sugar alcohol excipients (e.g. sorbitol, mannitol, xylitol, a
combination comprising at least one of the foregoing, and the
like), optionally combined with a disintegrant (e.g. the
disintegrant is selected from crospovidone, croscarmellose, sodium
starch glycolate, a combination comprising at least one of the
foregoing, and the like), and/or a glidant (e.g. colloidal silica,
silica gel, precipitated silica, a combination comprising at least
one of the foregoing, and the like). Suitable fast-dissolve can be
found in U.S. Patent Application Publication US20030118642 A1 to
Norman et al. incorporated herein in its entirety.
[0113] The tablets of a fast dissolving dosage form should rapidly
disintegrate when orally administered. By "rapid", it is understood
that the tablets should disintegrate in the mouth of a patient in
less than about 10 minutes, and desirably between about 30 seconds
and about 7 minutes, specifically the tablet should dissolve in the
mouth between about 30 seconds and about 5 minutes. Disintegration
time in the mouth can be measured by observing the disintegration
time of the tablet in water at about 37.degree. C. The tablet is
immersed in the water without forcible agitation. The
disintegration time is the time from immersion for substantially
complete dispersion of the tablet as determined by visual
observation. As used herein, the term "complete disintegration" of
the tablet does not require dissolution or disintegration of the
microcapsules or other discrete inclusions.
[0114] Fast-dissolve tablets can be manufactured by well-known
tableting procedures. In common tableting processes, the material
which is to be tableted is deposited into a cavity, and one or more
punch members are then advanced into the cavity and brought into
intimate contact with the material to be pressed, whereupon
compressive force is applied. The material is thus forced into
conformity with the shape of the punches and the cavity. Hundreds,
and even thousands, of tablets per minute can be produced in this
fashion.
[0115] Taste-masked solid dosage forms of quinine are useful since
quinine exhibits a particularly bitter taste. A solid taste-masked
dosage form comprises a core element comprising quinine or a salt
thereof and a coating surrounding the core element. The core
element comprising quinine or a salt thereof may be in the form of
a capsule or be encapsulated by micro-encapsulation techniques,
where a polymeric coating is applied to the formulation. The core
element can also include excipients, fillers, flavoring agents,
stabilizing agents and/or colorants.
[0116] The taste-masked dosage form may include about 77 wt % to
about 100 wt %, specifically about 80 wt % to about 90 wt %, based
on the total weight of the composition of a core element comprising
quinine or a salt thereof; and about 20 wt % to about 70 wt %, of a
substantially continuous coating on the core element formed from a
coating material including a polymer. The core element includes
about 52 wt % to about 85 wt % of quinine or a salt thereof; and
approximately 5 wt % to about 25 wt % of a supplementary component
selected from waxes, water insoluble polymers, enteric polymers,
and partially water soluble polymers, other suitable pharmaceutical
excipients, and a combination comprising at least one of the
foregoing components.
[0117] The coating material of the taste-masked formulation may
take a form which provides a substantially continuous coating and
still provides taste-masking. In some cases, the coating also
provides controlled-release of the active agent. The polymer used
in taste-masked dosage form coating may be a water insoluble
polymer such as, for example, ethyl cellulose. The coating material
of the taste-masked dosage form may further include a
plasticizer.
[0118] A method of preparing taste-masked pharmaceutical
formulations such as powdered formulations includes mixing a core
element and a coating material in a diluent and spray drying the
mixture to form a taste-masked formulation. Spray drying of the
active agent and polymer in the solvent involves spraying a stream
of air into an atomized suspension so that solvent is caused to
evaporate leaving the active agent coated with the polymer coating
material.
[0119] Liquid dosage forms of quinine or a salt thereof may be
formulated to provide adequate taste-masking as well as
extended-release properties. A taste-masked liquid dosage form may
comprise a suspension of taste-masked particles (e.g.,
microparticles). The use of polymeric coatings on the active agent
microparticles, which inhibit or retard the rate of dissolution and
solubilization of the active agent is one means of overcoming the
taste problems with delivery of active agents in suspension. The
polymeric coating allows time for all of the particles to be
swallowed before the taste threshold concentration is reached in
the mouth.
[0120] A taste-masked liquid dosage form thus comprises the active
agent, a polymer encapsulating the active agent, and a suspending
medium for suspending the encapsulated active agent. The active
agent can be taste-masked by the polymer or polymer and suspending
medium.
[0121] The quinine may be in the form of its neutral or salt form
and may be in the form of particles, crystals, microcapsules,
granules, microgranules, powders, pellets, amorphous solids or
precipitates. The particles may further include other functional
components. The quinine particles may have a defined particle size
distribution, specifically in the region of less than or equal to
about 1000 micrometers, specifically less than or equal to about
750 micrometers, more specifically less than or equal to about 500
micrometers, yet more specifically less than or equal to about 250
micrometers, and still yet more specifically less than or equal to
about 150 micrometers, where there is acceptable mouth feel and
little chance of chewing on the residual particles and releasing
the active agent to taste.
[0122] The taste-masked liquid dosage form may include, along with
quinine or a salt thereof, other functional components present for
the purpose of modifying the physical, chemical, or taste
properties of the quinine. For example the quinine may be in the
form of ion-exchange or cyclodextrin complexes or the quinine may
be included as a mixture or dispersion with various additives such
as waxes, lipids, dissolution inhibitors, taste-masking or
-suppressing agents, carriers or excipients, fillers, and a
combination comprising at least one of the foregoing components.
When used in such taste-masked formulations, the size of the
quinine salt particle can be of any size, from the molecular level,
up to about smicrometer size.
[0123] The pharmaceutically active agent or the active agent
particle may be suspended, dispersed or emulsified in the
suspending medium after encapsulation with the polymer. The
suspending medium may be a water-based medium, but may be a
non-aqueous carrier as well. The taste-masked liquid dosage form
may further include other optional dissolved or suspended agents to
provide stability to the suspension. These include suspending
agents or stabilizers such as, for example, methyl cellulose,
sodium alginate, xanthan gum, (poly)vinyl alcohol, microcrystalline
cellulose, colloidal silicas, bentonite clay, and a combination
comprising at least one of the foregoing agents. Other agents used
include preservatives such as methyl, ethyl, propyl and butyl
parabens, sweeteners such as sucrose, saccharin sodium, aspartame,
mannitol, flavorings such as grape, cherry, peppermint, menthol and
vanilla flavors, and antioxidants or other stabilizers, and a
combination comprising at least one of the foregoing agents.
[0124] Encapsulation of the microparticle or active agent particle
by the polymer may be performed by a method such as suspending,
dissolving, or dispersing in a solution or dispersion of polymer
coating material and spray drying, fluid-bed coating, simple or
complex coacervation, coevaporation, co-grinding, melt dispersion
and emulsion-solvent evaporation techniques, and the like.
[0125] The polymer coated quinine, or salt thereof, powder can also
as an alternative be applied for the preparation of reconstitutable
powders, ie; dry powder active agent products that are
reconstituted as suspensions or emulsions in a liquid vehicle such
as water before usage. The reconstitutable powders have a long
shelf life and the suspensions, once reconstituted, have adequate
taste-masking.
[0126] Suitable liquid taste-masked dosage forms include those
disclosed in U.S. Pat. No. 6,197,348.
[0127] The quinine or pharmaceutically acceptable salt thereof can
also be formulated into parenteral depot formulations. Parenteral
depot formulations are injected or implanted into the muscle or
subcutaneous tissue and release quinine in a controlled manner. An
advantage of depot forms is the sustained-release of quinine for
several days or weeks.
[0128] Such forms can be in the form of microparticles or implants
(e.g., rod-shaped). Implants are rod-shaped devices injected
through a large bore needle into the subcutaneous tissue.
Microparticies are generally spherical and can be injected
intramuscularly or subcutaneously as their size typically range
from about 1 to about 1000 micrometers, specifically about 10 to
about 100 micrometers. Microparticles can include i) microcapsules,
that is microparticles containing quinine in a core surrounded by a
polymeric membrane; and ii) microspheres, that is microparticles
containing the drug in a polymeric matrix, forming a solid
dispersion or solid solution.
[0129] The depot formulations can be prepared from biodegradable
polymer excipients or non-biodegradable polymer excipients. The
polymer excipient controls the rate of drug release and, if
biodegradable, resorbs during and/or after drug release.
[0130] Exemplary biodegradable polymers are lactide/glycolide
polymers, while an exemplary non-biodegradable polymer is ethylene
vinylacetate copolymer. Overall drug release may be controlled by
varying the polymer composition. For example, an increase in the
level of lactic acid in a lactide/glycolide polymer can retard drug
release and an increase in the polymer molecular weight also can
retard drug release and prolong drug effects in vivo.
[0131] Exemplary extended-release forms are described in U.S. Pat.
No. 5,102,666 incorporated herein by reference. As described
therein a polymeric composition comprises a reaction complex formed
by the interaction of (1) a calcium polycarbophil component which
is a water-swellable, but water insoluble, fibrous cross-linked
carboxy-functional polymer, the polymer containing (a) a plurality
of repeating units of which at least about 80% contain a carboxyl
functionality, and (b) about 0.05 to about 1.5% cross-linking agent
substantially free from polyalkenyl polyether, the percentages
being based upon the weights of unpolymerized repeating unit and
cross-linking agent, respectively, with (2) water, in the presence
of an active agent.
[0132] The amount of calcium polycarbophil present can be about 0.1
to about 99% by weight, for example about 10%. The amount of
quinine or a salt thereof present can be about 0.0001 to about 65%
by weight, for example about 5 to about 20% of the reaction
complex. The amount of water present can be about 5 to about 200%
by weight, for example about 5 to about 10%. The interaction is
carried out at a pH of between about 3 and about 10, for example
about 6 to 7. The calcium polycarbophil is originally present in
the form of a calcium salt containing about 5 to about 25%
calcium.
[0133] Several types of materials are suitable for forming the
polycarbophil type composition component. The polymer contains a
plurality of a repeating unit of which at least about 80 percent
contain a carboxyl functionality and about 0.05 to about 1.5
percent cross-linking agent substantially free from polyalkenyl
polyether, with the percentages being based upon the weights of the
unpolymerized repeating unit and cross-linking agent, respectively.
Specifically, at least about 90 percent of the repeating units
contain a carboxyl functionality, and more specifically, at least
95 percent of those repeating units contain a carboxyl
functionality. Still yet more specifically, this material is a
reaction product of the polymerization of only a
carboxyl-functional monomer and a cross-linking agent. More
specifically, this component contains about 0.1 to about 1 percent
by weight of polymerized cross-linking agent. The material also
contains from 5% to 25%, specifically 18% to 22% calcium as a
calcium salt of the polymer acid. Certain species of this type of
polymer is commercially available under the generic name "calcium
polycarbophil".
[0134] A calcium polycarbophil type composition polymer useful
herein may thus be defined as a reaction product of the
copolymerization of at least 80 weight percent monoethylenically
unsaturated carboxy-functional monomer and about 0.05 to about 1.5
weight percent of a cross-linking agent free of polyalkenyl
polyether and 18-22% of calcium.
[0135] In addition to the above two ingredients, the polycarbophil
type polymer may also include polymerized monoethylenically
unsaturated repeating units such as C.sub.1-C.sub.6 alkyl esters of
one or more of the above-described acids such as hexyl acrylate,
butyl methacrylate and methyl crotonate; hydroxyalkylene-functional
esters of the above-described acids that contain a per molecule
average of 1 to about 4 oxyalkylene groups containing 2-3 carbon
atoms such as hydroxyethyl methacrylate, hydroxypropyl acrylate and
tetraethylene glycol monoacrylate; methacrylamide, acrylamide and
their C.sub.1-C.sub.4 mono- and dialkyl derivatives such as
N-methyl acrylamide, N-butyl methacrylamide and N,N-dimethyl
acrylamide; styrene; and the like as are known in the art as being
copolymerizable with the above described carboxyl
functionality-containing monomers and cross-linking agents. The
polymers most specifically are prepared from only the
monoethylenically unsaturated carboxy-functional monomer and the
cross-linking agent.
[0136] The interaction of the calcium polycarbophil with the water
results in the formation of a complex hydrogel matrix structure
which then acts to control the diffusion or other transport of the
quinine or salt thereof within and from the matrix itself. The
desired level of controlled or sustained-release will vary,
depending upon the ratio of the components employed, the physical
state of the quinine or salt thereof, the method of incorporation,
the order of mixing of the components, and the like. Additional
additives may also be present which may modify the characteristics
of the matrix and its release properties.
[0137] In one embodiment, an extended-release formulation comprises
a polymeric composition comprising a reaction complex formed by the
interaction of water and a calcium polycarbophil component; wherein
the calcium polycarbophil component is a water-swellable, but water
insoluble, fibrous cross-linked carboxy-functional polymer
comprising (a) a plurality of repeating units of which at least
about 80% contain a carboxyl functionality, and (b) about 0.05 to
about 1.5% cross-linking agent substantially free from polyalkenyl
polyether, the percentages being based upon the weights of
unpolymerized repeating unit and cross-linking agent, respectively;
and wherein the reaction complex is formed in the presence of
quinine or a pharmaceutically acceptable salt thereof.
[0138] In another embodiment, a process for preparing an
extended-release formulation comprises combining, in the presence
of quinine or a pharmaceutically acceptable salt thereof, water and
a calcium polycarbophil component; wherein the calcium
polycarbophil component is a water-swellable, but water insoluble,
fibrous cross-linked carboxy-functional polymer, the fibrous
cross-linked carboxy-functional polymer comprises (a) a plurality
of repeating units of which at least about 80% contain a carboxyl
functionality, and (b) about 0.05 to about 1.5% cross-linking agent
substantially free from polyalkenyl polyether, the percentages
being based upon the weights of unpolymerized repeating unit and
cross-linking agent, respectively.
[0139] Additional exemplary extended-release forms are described in
U.S. Pat. No. 5,422,123 incorporated herein by reference. Described
therein are tablets consisting of a core of defined geometrical
form containing an active substance, polymer substances which swell
on contact with aqueous liquids, substances with gelling
properties, and possibly other substances with an adjuvant
function; and a support applied to the core to partly cover its
surface, and are characterized in that the support consists of
polymer substances which are slowly soluble and/or slowly gellable
in aqueous liquids, plasticizing substances, and possibly other
substances with an adjuvant function, which plasticizing action can
also be performed by the polymer substances.
[0140] The core can be prepared by compressing the core mixture
containing quinine or a salt thereof under a pressure of about 1000
to about 4000 kg/cm.sup.2 and therefore assumes a defined
geometrical form. Exemplary forms include a cylindrical tablet with
flat, convex, or concave bases.
[0141] Polymer materials suitable to prepare the core are those
which swell on contact with aqueous liquids, essentially insoluble
polymers are used such as crosslinked sodium
carboxymethylcellulose, crosslinked hydroxypropylcellulose, high
molecular weight hydroxypropylmethylcellulose, carboxymethyl
starch, potassium methacrylate/divinylbenzene copolymer,
polymethylmethacrylate, crosslinked polyvinylpyrrolidone, high
molecular weight polyvinylalcohols etc. Gellable polymer materials
include methylcellulose, carboxymethylcellulose, low molecular
weight hydroxypropylmethylcellulose, low molecular weight
polyvinylalcohols, polyethylene glycols, non-crosslinked
polyvinylpyrrolidone. Polymers which possess both swelling and
gelling properties such as medium viscosity
hydroxypropylmethylcellulose and medium viscosity polyvinylalcohols
can also be used. Adjuvant substances include mannitol,
ethylcellulose, magnesium stearate, colloidal silica and
others.
[0142] The ratio of polymer substances with swelling properties to
gellable polymer substances is between about 1:9 to about 9:1. The
active agent content in the core can be about 1 to about 95% by
weight based on the total weight of the core.
[0143] The support generally has a thickness of about 10
micrometers to about 4 millimeters depending on the hydrophilic
characteristics of the components, its task being to limit and
define the direction of release of the active substance contained
in the core. As the support is generally less hydrophilic than the
core and does not contain active agent, the transfer of active
agent can occur to a significant and immediate extent only from
that portion of the core which is not covered by the support.
[0144] Suitable materials that can be used to prepare the support
include support polymer substances slowly soluble and/or slowly
gellable in aqueous liquids, these substances being used either
alone or in mixture with each other, are chosen from the group
consisting of hydroxypropylmethylcellulose having a molecular
weight of about 4,000 to about 2,000,000, high molecular weight
carboxyvinylpolymers, polyvinylalcohols, scleroglucans, acrylates,
methacrylates, hydroxypropylcellulose, sodium
carboxymethylcellulose, and hydrophilic cellulose derivatives.
[0145] The support polymer substances are present in about 2 to
about 95 weight % and specifically about 30 to about 90 weight % of
the support composition. The support composition also includes
substances able to provide elasticity, such as polyethylene
glycols, castor oil, hydrogenated castor oil, ethyl phthalate,
butyl phthalate, and natural, synthetic and semisynthetic
glycerides, and the like. The support elasticity substances ensure
correct release kinetics, determined by the fact that the support
is sufficiently elastic to follow any change consequent on the
hydration of the core without causing cracking or gaps which would
result in total, and premature, release of the active agent.
[0146] These support elasticity substances can be present in zero
to about 50 weight % and specifically about 2 to about 15 weight %
of the total weight of the support.
[0147] Finally, the support composition can include binders such as
polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic,
alginic acid and its derivatives, hydrophilic agents such as
mannitol, lactose, starch, colloidal silica, and hydrophobic agents
such as hydrogenated castor oil, magnesium stearate, fatty
substances, waxes, and natural and synthetic glycerides. Choice of
hydrophilic and hydrophobic agents controls the hydrophilic
properties of the support and the desired release rate. The
binders, hydrophilic agents and hydrophobic agents can be present
in an amount of about zero to about 50 weight and specifically
about 0.5 to about 35 weight % of the total weight of the
support.
[0148] The components of the support are prepared by mixing,
possibly wetting with a binding solution in accordance with the
known art, then bringing the mixture to the dry granular state. The
mixture can be screened and mixed with other components until an
easily flowable homogeneous mixture is obtained. The prepared
support mixture is then applied to the core as a surface layer by
using presses. The support can be applied to one or two bases of
the core, or can be applied to the entire core surface with the
exception of one base, or to the entire lateral surface with the
exclusion of the two bases. The support is typically applied using
a pressure of about 1000 to about 4000 kg/cm.sup.2.
[0149] In one embodiment, an extended-release formulation comprises
(a) a deposit-core having a defined geometric form and comprising a
therapeutically effective amount of quinine or a pharmaceutically
acceptable salt thereof, and a core polymeric material selected
from the group consisting of (1) a swellable polymeric material
which swells on contact with water or aqueous liquids and a
gellable polymeric material, wherein the ratio of the swellable
polymeric material to gellable polymeric material is about 1:9 to
about 9:1, and (2) a single polymeric material having both swelling
and gelling properties; and (b) a support-platform applied to the
deposit-core, and wherein the support-platform is an elastic
support applied to the deposit-core so that it partially covers a
surface of the deposit-core and follows changes due to hydration of
the deposit-core and is slowly soluble and/or slowly gellable in
aqueous fluids.
[0150] The support-platform of this embodiment can comprise a
polymer substance which is slowly soluble or slowly gellable in
aqueous liquids and a plasticizing substance. The plasticizing
substance contained in the support-platform can be selected from
the group consisting of polyoxyethylene glycols, castor oil,
hydrogenated castor oil, ethyl phthalate, butyl phthalate, natural
glycerides, synthetic glycerides, and semisynthetic glycerides. The
plasticizing substance can be present at about 2 to about 15% by
weight of the total weight of the support-platform.
[0151] Furthermore, in this embodiment, the support-platform can
further comprise a binder selected from the group consisting of
polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic,
and alginic acid. The support-platform can comprise a hydrophilic
agent selected from the group consisting of mannitol, lactose,
starch, and colloidal silica. The support-platform can comprise a
hydrophobic agent selected from the group consisting of
hydrogenated castor oil, magnesium stearate, a fatty substance,
wax, natural glycerides, and synthetic glycerides.
[0152] Furthermore in this embodiment, the core polymeric material
can be selected from the group consisting of crosslinked sodium
carboxymethylcellulose, crosslinked hydroxypropylcellulose, high
molecular weight hydroxypropylmethylcellulose, carboxymethyl
starch, potassium methacrylate/divinylbenzene copolymer,
polymethylmethacrylate, crosslinked polyvinylpyrrolidone, high
molecular weight polyvinylalcohols, methylcellulose,
carboxymethylcellulose, low molecular weight
hydroxypropylmethylcellulose, low molecular weight
polyvinylalcohols, polyethylene glycols, non-crosslinked
polyvinylpyrrolidone, medium viscosity
hydroxypropylmethylcellulose, medium viscosity polyvinylalcohols,
and a combination comprising at least one of the foregoing.
[0153] In another embodiment, a process for preparing an
extended-release formulation comprises granulating deposit-core
ingredients to form a core granular mixture, wherein the
deposit-core ingredients comprise a therapeutically effective
amount of quinine or a pharmaceutically acceptable salt thereof,
and a core polymeric material selected from the group consisting of
(1) a swellable polymeric material which swells on contact with
water or aqueous liquids and a gellable polymeric material, wherein
the ratio of the swellable polymeric material to gellable polymeric
material is about 1:9 to about 9:1, and (2) a single polymeric
material having both swelling and gelling properties; compressing
the core granular mixture to form a deposit-core of a defined
geometrical form; screening and mixing support-platform components
to obtain a support granular mixture, wherein the support-platform
components comprise a polymer substance which is slowly soluble or
slowly gellable in aqueous liquids, and a plasticizing substance;
and applying the support granular mixture onto a portion of a
surface of the deposit-core by compressing to form the
support-platform partially covering the deposit-core of defined
geometrical form.
[0154] As used herein, "pharmaceutically acceptable excipient"
means any other component added to the pharmaceutical formulation
other than the active agent. Excipients may be added to facilitate
manufacture, enhance stability, control release, enhance product
characteristics, enhance bioavailability, enhance patient
acceptability, etc. Pharmaceutical excipients include carriers,
fillers, binders, disintegrants, lubricants, glidants, compression
aids, colors, sweeteners, preservatives, suspending agents,
dispersing agents, film formers, flavors, printing inks, etc.
[0155] Binders hold the ingredients in the dosage form together.
Exemplary binders include, for example, polyvinyl pyrrolidone,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose and hydroxyethyl cellulose, sugars, and a
combination comprising at least one of the foregoing binders.
[0156] Disintegrants expand when wet causing a tablet to break
apart. Exemplary disintegrants include water swellable substances,
for example, low-substituted hydroxypropyl cellulose, e.g. L-HPC;
cross-linked polyvinyl pyrrolidone (PVP-XL), e.g. Kollidon.RTM. CL
and Polyplasdone.RTM. XL; cross-linked sodium
carboxymethylcellulose (sodium croscarmellose), e.g.
Ac-di-sol.RTM., Primellose.RTM.; sodium starch glycolate, e.g.
Primojel.RTM.; sodium carboxymethylcellulose; sodium carboxymethyl
starch, e.g. Explotab.RTM.; ion-exchange resins, e.g. Dowex.RTM. or
Amberlite.RTM.; microcrystalline cellulose, e.g. Avicel.RTM.;
starches and pregelatinized starch, e.g. Starch 1500.RTM.;
formalin-casein, and a combination comprising at least one of the
foregoing water swellable substances.
[0157] Lubricants, for example, aid in the processing of powder
materials. Exemplary lubricants include calcium stearate, glycerol
behenate, magnesium stearate, mineral oil, polyethylene glycol,
sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc
stearate, and a combination comprising at least one of the
foregoing lubricants. Glidants include, for example, silicon
dioxide.
[0158] Certain dosage forms described herein contain a filler, such
as a water insoluble filler, water soluble filler, and a
combination comprising at least one of the foregoing. The filler
may be a water insoluble filler, such as silicon dioxide, titanium
dioxide, talc, alumina, starch, kaolin, polacrilin potassium,
powdered cellulose, microcrystalline cellulose, and a combination
comprising at least one of the foregoing fillers. Exemplary
water-soluble fillers include water soluble sugars and sugar
alcohols, specifically lactose, glucose, fructose, sucrose,
mannose, dextrose, galactose, the corresponding sugar alcohols and
other sugar alcohols, such as mannitol, sorbitol, xylitol, and a
combination comprising at least one of the foregoing fillers.
[0159] The dosage form can be prepared by various conventional
mixing, comminution and fabrication techniques readily apparent to
those skilled in the art of drug formulations. Examples of such
techniques include direct compression, using appropriate punches
and dies, the punches and dies are fitted to a suitable rotary
tableting press; injection or compression molding using suitable
molds fitted to a compression unit, granulation followed by
compression; and extrusion in the form of a paste, into a mold or
to an extrudate to be cut into lengths.
[0160] Oral dosage forms may be prepared to include an effective
amount of melt-extruded subunits in the form of multiparticles
within a capsule. For example, a plurality of the melt-extruded
muliparticulates can be placed in a gelatin capsule in an amount
sufficient to provide an effective release dose when ingested and
contacted by gastric fluid.
[0161] The subunits, e.g., in the form of multiparticulates, can be
compressed into an oral tablet using conventional tableting
equipment using standard techniques. Techniques and compositions
for making tablets (compressed and molded), capsules (hard and soft
gelatin) are also described in Remington's Pharmaceutical Sciences,
(Aurther Osol., editor), 1553-1593 (1980).
[0162] The composition may be in the form of micro-tablets enclosed
inside a capsule, e.g. a gelatin capsule. For this, a gelatin
capsule employed in the pharmaceutical formulation field can be
used, such as the hard gelatin capsule known as CAPSUGEL, available
from Pfizer.
[0163] Certain dosage forms described herein may be coated. The
coating can be a suitable coating, such as, a functional or a
non-functional coating, or multiple functional and/or
non-functional coatings. By "functional coating" is meant to
include a coating that modifies the release properties of the total
formulation, for example, an extended-release coating. By
"non-functional coating" is meant to include a coating that is not
a functional coating, for example, a cosmetic coating. A
non-functional coating can have some impact on the release of the
active agent due to the initial dissolution, hydration, perforation
of the coating, etc., but would not be considered to be a
significant deviation from the non-coated composition.
[0164] The dosage forms described herein may be coated with a
functional or non-functional coating. The coating may comprise
about 0 wt % to about 40 wt % of the composition. The coating
material may include a polymer, specifically a film-forming
polymer, for example, methyl cellulose, ethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
hydroxybutyl methyl cellulose, cellulose acetate, cellulose
propionate, cellulose acetate propionate, cellulose acetate
butyrate, cellulose acetate phthalate, carboxymethyl cellulose,
cellulose triacetate, cellulose sulphate sodium salt, poly(methyl
methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),
poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene),
poly(ethylene) low density, poly (ethylene) high density, (poly
propylene), poly(ethylene glycol, poly(ethylene oxide),
poly(ethylene terephthalate), poly(vinyl alcohol), poly(vinyl
isobutyl ether), poly(viny acetate), poly(vinyl chloride),
polyvinyl pyrrolidone, and a combination comprising at least one of
the foregoing polymers.
[0165] To provide a taste-masking effect, the polymer can be a
water-insoluble polymer. Water insoluble polymers include ethyl
cellulose or dispersions of ethyl cellulose, acrylic and/or
methacrylic ester polymers, cellulose acetates, butyrates or
propionates or copolymers of acrylates or methacrylates having a
low quaternary ammonium content, and the like, and a combination
comprising at least one of the foregoing polymers.
[0166] The inclusion of an effective amount of a plasticizer in the
coating composition can improve the physical properties of the
film. For example, because ethyl cellulose has a relatively high
glass transition temperature and does not form flexible films under
normal coating conditions, it may be advantageous to add
plasticizer to the ethyl cellulose before using the same as a
coating material. Generally, the amount of plasticizer included in
a coating solution is based on the concentration of the polymer,
e.g., most often from about 1 wt % to about 50 wt % of the polymer.
Concentrations of the plasticizer, however, can be determined by
routine experimentation.
[0167] Examples of plasticizers for ethyl cellulose and other
celluloses include plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, triacetin, and a
combination comprising at least one of the foregoing plasticizers,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) can be used.
[0168] Examples of plasticizers for acrylic polymers include citric
acid esters such as triethyl citrate NF, tributyl citrate, dibutyl
phthalate, 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, triacetin, and a combination
comprising at least one of the foregoing plasticizers, although it
is possible that other plasticizers (such as acetylated
monoglycerides, phthalate esters, castor oil, etc.) can be
used.
[0169] An example of a functional coating comprises a coating agent
comprising a poorly-water-permeable component (a) such as, an alkyl
cellulose, for example an ethylcellulose, such as AQUACOAT (a 30%
dispersion available from FMC, Philadelphia, Pa.) or SURELEASE (a
25% dispersion available from Colorcon, West Point, Pa.) and a
water-soluble component (b), e.g., an agent that can form channels
through the poorly-water-permeable component upon the hydration or
dissolution of the soluble component. Specifically, the
water-soluble component is a low molecular weight, polymeric
material, e.g., a hydroxyalkylcellulose,
hydroxyalkyl(alkylcellulose), and carboxymethylcellulose, or salts
thereof. Particular examples of these water soluble polymeric
materials include hydroxyethylcellulose, hydroxypropylcellulose,
hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose, and a
combination comprising at least one of the foregoing materials. The
water-soluble component can comprise hydroxypropylmethylcellulose,
such as METHOCEL (Dow). The water-soluble component can be of
relatively low molecular weight, specifically less than or equal to
about 25,000 molecular weight, or specifically less than or equal
to about 21,000 molecular weight.
[0170] In the functional coating, the total of the water soluble
portion (b) and poorly-water permeable portion (a) are present in
weight ratios (b):(a) of about 1:4 to about 2:1, specifically about
1:2 to about 1:1, and more specifically in a ratio of about 2:3.
While the ratios disclosed herein are preferred for duplicating
target release rates of presently marketed dosage forms, other
ratios can be used to modify the speed with which the coating
permits release of the active agent. The functional coating may
comprise about 1 wt % to about 40 wt %, specifically about 3 wt %
to about 30 wt %, more specifically about 5 wt % to about 25 wt %,
and yet more specifically about 6 wt % to about 15 wt % of the
total formulation.
[0171] Suitable methods can be used to apply the coating to the
dosage forms. Processes such as simple or complex coacervation,
interfacial polymerization, liquid drying, thermal and ionic
gelation, spray drying, spray chilling, fluidized bed coating, pan
coating, electrostatic deposition, may be used.
[0172] The coatings may be of any thickness, specifically about
0.005 micrometers to about 25 micrometers thick and more
specifically about 0.05 micrometers to about 5 micrometers.
[0173] As disclosed herein, the exemplary dosage forms (e.g.
containing extended-release quinine particles) exhibit a
pharmacokinetic profile that has a fast onset and level peak and
trough values. The dosage forms can be formulated to provide a
dissolution profile that is substantially pH independent or,
alternatively, pH dependent (e.g. enteric coated forms).
[0174] In one embodiment, the dosage form exhibits a dissolution
profile such that at 60 minutes after combining the dosage form
with 900 ml of purified water at 37.degree. C..+-.0.5.degree. C.
according to USP 28<711> test method 2 (paddle), 75 rpm
paddle speed, about 20 to about 40 weight percent of the total
amount of quinine is released, and wherein after 10 hours greater
than or equal to about 80% of the total amount of quinine is
released.
[0175] In another embodiment, the dosage form exhibits a
dissolution profile such that at 60 minutes after combining the
dosage form with 900 ml of purified water at 37.degree.
C..+-.0.5.degree. C. according to USP 28<711> test method 2
(paddle), 75 rpm paddle speed, about 10 to about 30 weight percent
of the total amount of quinine is released, and wherein after 10
hours greater than or equal to about 70% of the total amount of
quinine is released.
[0176] In yet another embodiment, the dosage form exhibits a
dissolution profile such that at 2 hours after combining the dosage
form with 0.1 N Hydrochloric Acid medium at 37.degree.
C..+-.0.5.degree. C. according to USP 28<711> test method 1
or 2, about 0 to about 10 weight percent of the total amount of
quinine is released and wherein after 2 hours when the medium is
switched to a buffer phase of pH 4.5, 6.8, 7.0 or water, about 0 to
about 100 weight percent of the total amount of quinine is
released.
[0177] In another embodiment, the dosage form exhibits a
dissolution profile such that at 2 hours after combining the dosage
form with 0.1 N Hydrochloric Acid medium at 37.degree.
C..+-.0.5.degree. C. according to USP 28<711> test method 1
or 2, about 0 to about 50 weight percent of the total amount of
quinine is released and wherein after 2 hours when the medium is
switched to a buffer phase of pH 4.5, 6.8, 7.0 or water, about 0 to
about 100 weight percent of the total amount of quinine is
released.
[0178] In another embodiment, the extended-release quinine
formulation can reach T.sub.max at about 1.5 to about 8 hours,
specifically about 3 to about 7 hours, and more specifically about
5 to about 6 hours. After dosing an extended-release quinine
formulation containing about 300-600 mg quinine the C.sub.max is
about 200 to about 7000 ng/mL, specifically about 500 to 5000
ng/mL, and more specifically about 1000 to about 3000 ng/mL; and
the C.sub.min is about 100 to about 3500 ng/mL at 12 to 24 hours,
when at steady state.
[0179] In yet another embodiment, the extended-release quinine
formulation exhibits a pharmacokinetic profile wherein the duration
of 50% or greater of C.sub.max is about 10 to about 20 hours.
Furthermore, the extended-release quinine formulation exhibits a
pharmacokinetic profile wherein the duration of 80% or greater of
C.sub.max is about 2 to about 12 hours.
[0180] The formulations according deliver a therapeutically
effective amount of quinine to a patient during the 16,
specifically 18, and more specifically 24 hours following a single
once daily administration.
[0181] In one embodiment, the extended-release quinine formulation
exhibits greater bioavailability than a corresponding
immediate-release formulation. Therefore, the extended-release
formulation allows for the use of lower amounts of active agent
while exhibiting the same bioequivalence as higher doses found in
immediate-release forms.
[0182] In one embodiment, an extended-release quinine solid oral
dosage form can comprise about 50 to about 1000 mg of quinine, more
specifically about 100 to about 750 mg of quinine, and yet more
specifically about 250 to about 500 mg of quinine base equivalent
per dosage unit.
[0183] In one embodiment, an extended-release quinine solid oral
dosage form can comprise about 350 to about 520 mg of quinine, more
specifically about 450 to about 500 mg of quinine, and yet more
specifically about 475 to about 490 mg of quinine base equivalent
per dosage unit taken as two units three times a day, two or three
units twice a day, or three or four units once a day.
[0184] In another embodiment, an extended-release quinine solid
oral dosage form can comprise about 100 to about 400 mg of quinine,
more specifically about 150 to about 350 mg of quinine, and yet
more specifically about 200 to about 300 mg of quinine base
equivalent per dosage unit taken as one, two, three, or four units
once, twice, or three times a day.
[0185] In yet another embodiment, an extended-release quinine solid
oral dosage form can comprise about 200 to about 600 mg of quinine
sulfate, more specifically about 260 to about 520 mg of quinine
sulfate, and yet more specifically about 300 to about 450 mg of
quinine sulfate per dosage unit.
[0186] Also included herein are pharmaceutical kits useful, for
example, for the treatment of parasitic diseases (e.g.
uncomplicated Plasmodium falciparum malaria, severe or complicated
Plasmodium falciparum malaria) caused by Plasmodium species (e.g.
sp. Falciparum, Plasmodium falciparum), the treatment and
prophylaxis of leg cramps, or the treatment of babesiosis caused by
Babesia microti, which comprise one or more containers containing
an extended-release form of quinine or a salt thereof. The kits may
further comprise one or more conventional pharmaceutical kit
components, such as, for example, one or more containers to aid in
facilitating compliance with a particular dosage regimen; one or
more carriers; printed instructions, either as inserts or as
labels, indicating quantities of the components to be administered,
and/or guidelines for administration. Exemplary kits can be in the
form of bubble or blister pack cards, optionally arranged in a
desired order for a particular dosing regimen. Suitable blister
packs that can be arranged in a variety of configurations to
accommodate a particular dosing regimen are well known in the art
or easily ascertained by one of ordinary skill in the art.
[0187] In one embodiment, the controlled-release quinine
formulation is packaged with information warning that quinine may
cause QT/QTc prolongation as an adverse reaction in some
patients.
[0188] Those forms existing as liquids, solutions, emulsions, or
suspensions can be packaged for convenient dosing of pediatric or
geriatric patients. For example, prefilled droppers (such as eye
droppers or the like), prefilled syringes, and similar containers
housing the liquid, solution, emulsion, or suspension form of the
extended-release quinine formulation are contemplated.
[0189] In one embodiment, when the controlled-release quinine
formulation comprises carboxy vinyl polymer, the formulation is
free of polyethylene glycol, specifically a polyethylene glycol
having a molecular weight of about 900 to about 25,000. In another
embodiment, the controlled-release quinine formulation is free of a
polymer or crosslinker comprising thiol groups. In yet another
embodiment, the controlled-release quinine formulation is free of
the combination of a low molecular weight polyethylene oxide (e.g.
from about 100,000 to about 900,000), a high molecular weight
polyethylene oxide (e.g. MW from about 1,000,000 to about
9,000,000) and a starch or starch derivative. In still yet another
embodiment, when the controlled-release quinine formulation
contains a biodegradable polymer, the formulation is free of
chemotherapeutic agents. In still yet another embodiment, the
controlled-release quinine formulation is free of Eudragit RS, a
copolymer of acrylic acid and methacrylic acid esters containing
about 4 to about 7% ammonio groups.
[0190] In yet another embodiment, the controlled-release quinine
formulation contains no microcapsules encapsulated, coated, or
surrounded by an anionic or cationic polymer. In one embodiment,
the controlled-release quinine formulation contains only a
controlled-release portion and no immediate-release portion. In one
embodiment, the controlled-release quinine formulation comprises
(meth)acrylic and (meth)acrylate copolymers and polymers that are
free of tertiary amino groups. In one embodiment, the
controlled-release quinine formulation is free of pectin. In
another embodiment, the controlled-release quinine formulation is
free of a copolymer of polyvinyl alcohol and (meth)acrylic
acid.
[0191] In still yet another embodiment, the controlled-release
quinine formulation is free of a hydroxypropyl methylcellulose
matrix or a matrix containing a 1:1 combination of hydroxypropyl
methylcellulose and carboxymethyl cellulose matrix. In one
embodiment, the controlled-release quinine formulation comprises
quinine as the only active agent. In one embodiment, the
controlled-release quinine formulation is not in the form of a
liposome. In another embodiment, the controlled-release quinine
formulation does not contain lipid-encapsulated particles. In still
yet another embodiment, the controlled-release quinine formulation
is not a tablet comprising a coating prepared from latex aqueous
dispersions of acrylic polymers e.g. Eudragit L 100-55, Eudragit L
100, or Eudragit S 100; or emulsion polymers Eudragit L 30D or
Eudragit E 30D.
[0192] In one embodiment, the administration of a
controlled-release quinine formulation to a patient causes the
patient to experience a prolongation in the mean QT/QTc interval
from baseline of less than about 20 ms, specifically less than
about 10 ms, and more specifically less than about 5 ms.
[0193] In one embodiment, the therapeutically effective amount of
quinine in the controlled-release formulation is an amount
sufficient to significantly reduce the treated patient's risk of
experiencing prolongation of the heart's QT interval or other
adverse side effects as outline previously, while at the same time
providing the desired therapeutic effect. A significant reduction
is any detectable negative change that is statistically significant
in a standard parametric test of statistical significance such as
Student's T-test, where p<0.05.
[0194] The following examples further illustrate the invention but,
of course, should not be construed as in any way limiting its
scope.
EXAMPLES
Example 1
Extended-Release Formulation of Quinine Sulfate, Dihydrate
(cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, Sulfate (2:1),
Dihydrate)
Example 1
[0195] TABLE-US-00001 Ingredient Weight (mg) Weight (mg) Quinine
sulfate dihydrate 490 650 Carbopol 971P NF polymer 460 500 Lactose
monohydrate 40 40 Talc 5 5 Lubricant Magnesium Stearate 5 5 Total
1000 1200
[0196] The ingredients excluding the lubricant are mixed in a high
shear granulator. Water is added and the mixture wet granulated.
The granulation is screened, dried, and milled. The granulation is
added into a low shear blender, the lubricant is added, and
blended. The final blend is compressed on a tablet press to form
extended-release quinine dosage forms.
Example 2
[0197] TABLE-US-00002 Ingredient Weight (mg) Weight (mg) Quinine
sulfate dihydrate 490 650 Hydroxypropylmethylcellulose 460 500
Lactose monohydrate 40 40 Glidant Colloidal Silicon Dioxide 5 5
Lubricant Magnesium Stearate 5 5 Total 1000 1200
[0198] The ingredients excluding the lubricant and glidant are
mixed in a low shear blender for 20 minutes. The lubricant and
glidant are added and blended for 5 minutes. The formulation is
directly compressed on a tablet press.
Example 3
[0199] TABLE-US-00003 Ingredient Weight (mg) Weight (mg) Quinine
sulfate dihydrate 490 650 Hydroxypropylmethylcellulose 200 250
Hydroxyethylcellulose 260 290 Lactose monohydrate 40 0 Glidant
Colloidal Silicon Dioxide 5 5 Lubricant Magnesium Stearate 5 5
Total 1000 1200
[0200] The ingredients excluding the lubricant are mixed in a high
shear granulator. Water and ethyl alcohol are added as a
granulating solution and the mixture wet granulated. The
granulation is screened, dried, and milled. The granulation is
added into a low shear blender, the glidant and lubricant are
added, and blended. The final blend is compressed on a tablet
press.
Example 4
Pellets or Beads with a Modified-Release Coating
[0201] TABLE-US-00004 Ingredient Weight(g) Quinine sulfate
dihydrate 9000 Microcrystalline Cellulose 800 Lubricant Magnesium
Stearate 200 Total 10,000
[0202] The ingredients excluding the lubricant are mixed in a high
shear blender for 10 minutes. The lubricant is added and blended
for 3 minutes. The formulation is directly compressed into tablets
or pellets or beads. The pellets or beads can also be manufactured
by extrusion spheronization in which a wet mass of the composition
is extruded alone or with the aid of fillers, glidants, or
lubricants.
[0203] Modified Release Coating TABLE-US-00005 Ingredient %
Methacrylic Acid Copolymer 15 Polyethylene Glycol 600 1 Talc 4
Water/Ethyl Alcohol 80 Removed in process
[0204] Polyethylene glycol is added to a Water/Ethyl Alcohol
dispersion of Methacrylic Acid Copolymer and mixed. Talc is added
while stirring with a propeller mixer.
[0205] The pellets or beads are added into a perforated coating pan
or a fluid bed with a Wurster insert. The coating is sprayed onto
the pellets or beads. A coating level of about 5-20% coat weight is
applied.
[0206] The coated pellet or beads are filled into capsule
shells.
Example 5
Extended-Release Wax Formulation
[0207] TABLE-US-00006 Ingredient Weight(mg) Weight (mg) Quinine
sulfate dihydrate 490 650 Carnauba Wax 460 500 Microcrystalline
Cellulose 40 40 Glidant Colloidal Silicon Dioxide 5 5 Lubricant
Magnesium Stearate 5 5 Total 1000 1200
[0208] The ingredients excluding the lubricant and glidant are
mixed in a high shear granulator. Water and ethyl alcohol are added
and the mixture wet granulated. The granulation is screened, dried,
and milled. The granulation is added into a low shear blender, the
glidant and lubricant are added, and blended. The final blend is
compressed on a tablet press.
Example 6
QTc Interval Measurements Following Single Doses of Quinine
Sulfate
[0209] Studies were performed in healthy volunteers to measure QTc
intervals following single doses of quinine sulfate. One study
explored the effect of food on a single oral dose of a 324 mg oral
capsule (324 mg quinine sulfate, 82 mg corn starch, 40 mg talc, 4
mg magnesium stearate). A second study was performed to compare two
dose levels, a single oral dose of 324 mg quinine sulfate versus a
single oral dose of 648 mg quinine sulfate (two capsules), both
cases under fasting conditions. Repeated measurements of
Electrocardiogram (ECG) intervals were taken for 50 subjects, 24
men and 26 women, who ranged in age from 18 to 47 years. The
results are provided in Table 1 below and in FIGS. 1-4, which
illustrate the correlation of mean maximum QTc interval
prolongation effect to mean peak plasma quinine concentration.
TABLE-US-00007 TABLE 1 Study 1 Study 1 Study 2 Study 2 A: 324 mg B:
324 mg C: 324 mg D: 648 mg Quinine Sulfate Quinine Sulfate Quinine
Sulfate Quinine Sulfate capsule, Fasting capsule, Fed capsule,
fasting capsules, fasting conditions conditions conditions
conditions Time Mean Plasma Concentration (ng/ml); QTc (msec)
(hours) (ng/ml) (msec) (ng/ml) (msec) (ng/ml) (msec) (ng/ml) (msec)
0 0 399 0 397 0; 404 0 410 2 2040 402 835 397 1860 415 2808 422 4
1971 399 2265 396 1877 414 2946 422 6 1718 400 2013 402 1707 411
2721 419 12 990 398 1216 400 994 411 1705 417 24 473 399 543 400
475 409 912 412
[0210] The data provided in columns A and B of Table 1 are directed
to the mean plasma concentrations and QTc measurements over
24-hours following a single oral dose of a 324 mg Quinine Sulfate
capsule under fasting (A) and fed (B) conditions. The data provided
in column C of Table 1 are directed to the mean plasma
concentrations and QTc measurements over 24-hours following a
single oral dose of one 324 mg Quinine Sulfate capsule under
fasting conditions. The data provided in column D of Table 1 are
directed to the mean plasma concentrations and QTc measurements
over 24-hours following a single oral dose of two 324 mg Quinine
Sulfate capsule under fasting conditions.
[0211] As indicated by the data in the table, an increase in the
mean QTc value was found to correspond with the peak quinine plasma
concentration, which is reached in an average of 2.4 to 4.4 hours
after oral administration in the fasted state and 4 to 6 hours when
given with food was observed. Increases are higher when the same
dose is given with food (which results in higher peak
concentrations) and with a single dose of 648 mg as compared to 324
mg. In the study, seven subjects had significant prolongations in
QTc interval (>450 msec). As illustrated, the higher the blood
levels of quinine, the higher the incidence of QTc prolongation was
observed. Not wishing to be bound by theory, but by leveling the
blood level of quinine with little or no spiking of the blood
plasma concentration, the incidence of QTc prolongation may be
reduced or eliminated.
Example 7
Non-Linear Dose Proportionality Following Single Doses of Quinine
Sulfate
[0212] A study was performed in healthy volunteers to measure the
AUC (0-24 hours and 0-INF) and C.sub.max following single oral
doses of 1 and 2 capsules, each containing 324 mg quinine sulfate
(324 mg quinine sulfate, 82 mg corn starch, 40 mg talc, 4 mg
magnesium stearate per capsule), in the fasted state. The study was
performed on 24 subjects. After administration of the doses, blood
samples were taken from the subjects every half hour for the first
four hours and then every hour up to 48 hours. The results were
calculated as Ln-transformed data, geometric mean, as well as the
least squares mean, non-transformed data. The geometric means are
based on least squares means of ln-transformed values. The results,
provided in Table 2a below, indicate that there is nonlinear dose
proportionality where doubling the dose produces a C.sub.max that
is lower than would be expected with linear dose proportionality
under fasted conditions. C.sub.max resulted from multiplying plasma
concentration by 2 for the 1 capsule treatment is summarized in
Table 2a, and is 129% of that from the 2 capsule treatment with the
90% confidence interval from 122-138%. AUCT and AUC.sub.inf showed
proportional increase when given two capsules. TABLE-US-00008 TABLE
2a 324 mg Quinine Sulfate, 648 mg 90% Confidence 1 capsule* Quinine
Interval P-values for PK (dose adjusted to Sulfate, 2 (Lower Limit,
Product variable 2 .times. 324 mg) capsules* % Ratio Upper Limit)
Effects Ln-transformed data, Geometric Mean C.sub.max 4126.31
3174.89 129.97 (122.15, 138.29) <0.0001 (ng/ml) AUC.sub.0-t
61186.53 54440.26 112.39 (106.56, 118.54) 0.0011 (ng- hr/ml)
AUC.sub.0-INF 66715.41 59166.93 112.76 (105.69, 120.3) 0.0044 (ng-
hr/ml) Non-transformed data, least squares mean Cmax 4247.02
3243.11 130.96 (123.28, 138.63) <0.0001 (ng/ml) AUC.sub.0-t
64277.02 56394.65 113.98 (108.03, 119.93) 0.0006 (ng- hr/ml)
AUC.sub.0-INF 70886.14 61817.27 114.67 (107.37, 121.97) 0.0023 (ng-
hr/ml) Tmax 2.78 2.80 99.25 (84.8, 113.7) 0.9298 k.sub.elim 0.0592
0.0572 103.48 (94.67, 112.28) 0.5045 t.sub.1/2 12.76 12.80 99.67
(85.69, 113.66) 0.9683 *The capsules contained quinine sulfate USP,
corn starch, magnesium stearate, and talc.
Example 8
Dose Proportionality Following Single, Low Doses of Quinine
Sulfate
[0213] A pediatric study was performed in healthy volunteers to
measure the AUC (0-24 hours and 0-NF) and C.sub.max following
single oral doses of 260 mg quinine sulfate and 324 mg quinine
sulfate (1.25 times the lower dose of 260 mg), in the fasted state.
The study was performed on 22 subjects. After administration of the
doses, blood samples were taken from the subjects every half hour
for the first four hours, every hour up to 8 hours, and then at
hours ten, twelve, sixteen, twenty-four, thirty-six, and
forty-eight. The results were calculated as Ln-transformed data,
geometric mean, as well as the least squares mean, non-transformed
data. The geometric means are based on least squares means of
Ln-transformed values. The results, provided in Table 2b below,
indicate that there is linear dose proportionality when dosing
quinine sulfate at the lower doses of 260 mg and 324 mg.
TABLE-US-00009 TABLE 2B 260 mg Quinine Sulfate, 324 mg 90%
Confidence 1 capsule* Quinine Interval P-values for PK (dose
adjusted to Sulfate, 1 (Lower Limit, Product variable 1.25 .times.
324 mg) capsules* % Ratio Upper Limit) Effects Ln-transformed data,
Geometric Mean C.sub.max 2251.55 2242.70 100.39 (95.8, 105.21)
0.8861 (ng/ml) AUC.sub.0-t 30019.28 30318.55 99.01 (93.83, 104.48)
0.7535 (ng-hr/ml) AUC.sub.0-INF 32072.92 32111.76 99.88 (94.4,
105.67) 0.9708 (ng-hr/ml) Non-transformed data, least squares mean
Cmax 2310.90 2275.46 101.56 (95.93, 107.19) 0.6384 (ng/ml)
AUC.sub.0-t 31285.26 31298.12 99.96 (94.63, 105.28) 0.9895
(ng-hr/ml) AUC.sub.0-INF 33582.46 33280.89 100.91 (95.36, 106.46)
0.7811 (ng-hr/ml) Tmax 2.61 2.75 95.04 (84.53, 105.55) 0.4255
k.sub.elim 0.0615 0.0668 92.05 (85, 99.04) 0.0641 t.sub.1/2 11.94
11.13 107.27 (100.34, 114.2) 0.0856 *The capsules contained quinine
sulfate USP, corn starch, magnesium stearate, and talc.
[0214] Based on the results of Examples 7-8 illustrating non-dose
proportionality for the higher dosage of quinine and the dose
proportionality for the lower dosage, it is suggested that there is
a need for controlled-release forms to achieve lower and more
sustained plasma levels. By controlling the release of the quinine,
sharp plasma peaks and troughs can be avoided thereby providing a
safer profile for the administration of quinine.
[0215] The terms "a" and "an" do not denote a limitation of
quantity, but rather denote the presence of at least one of the
referenced item. The term "or" means "and/or". The terms
"comprising", "having", "including", and "containing" are to be
construed as open-ended terms (i.e., meaning "including, but not
limited to"). The endpoints of all ranges directed to the same
component or property are inclusive and independently combinable.
All methods described herein can be performed in a suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided herein, is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention unless otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention as used
herein, the terms wt %, weight percent, percent by weight, etc. are
equivalent and interchangeable.
[0216] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
* * * * *
References